Methods of using novel compounds as neuro-protective agents

ABSTRACT

This invention relates to novel phenyl oxazoles, thiazoles, oxazolines, oxadiazoles and benzoxazoles useful as neuro-protective agents.

This application is a division of application Ser. No. 10/109,133 filedMar. 27, 2002, now U.S. Pat. No. 6,472,387 Oct. 29, 2002, which is adivision of application Ser. No. 09/996,005 filed Nov. 28, 2001, nowU.S. Pat. No. 6,423,709 Jul. 23, 2002, which is a division ofapplication Ser. No. 09/715,987 filed on Nov. 17, 2000, now U.S. Pat.No. 6,380,213, which is a division of application Ser. No. 09/368,236filed on Aug. 4, 1999, now U.S. Pat. No. 6,166,216, which is a divisionof application Ser. No. 08/944,468 filed Oct. 6, 1997, now U.S. Pat. No.6,156,748, which claims priority to U.S. Provisional Application No.60/027,560 filed Oct. 7, 1996.

FIELD OF THE INVENTION

This invention relates to novel phenyl oxazoles, thiazoles, oxazolines,oxadiazoles and benzoxazoles useful as neuro-protective agents.

BACKGROUND OF THE INVENTION

Neurodegenerative processes can involve diverse areas of the CentralNervous System (CNS). Neurodegeneration appears clinically as abreakdown of functionally connected neuronal circuits with correspondingalterations in the neurotransmitter system and morphologicalorganization of the affected cell system.

The normal functioning of the CNS presupposes a well-balancedinteraction between different biochemical and structurally linkedneuronal systems. When one member of a neuronal circuit is altered inits structural or biochemical entity, an imbalance in the functionalsystem results and a compensatory mechanism must be activated in orderto maintain physiological equilibrium.

Perhaps the most severe form of neurodegeneration is that seen afterstroke. This form of cerebral ischemia results in the death of neurons,as well as glial cells and vascular elements of the brain. Quite often astroke results in paralysis, memory loss, inability to communicate, andeven death. Reactive oxygen intermediates are believed to play a role incausing brain death in stroke victims. Another form of cerebral ischemiathat can be quite devastating to important groups of selectivelyvulnerable neurons, is global ischemia. Global cerebral ischemia iscommonly seen in victims of cardiac arrest during the period of time theheart is undergoing fibrillation. Neuronal death from global ischemia isa common occurrence in heart attack victims that undergo cardiac arrestand cardiac arrest is a common occurrence in heart attack patients.Reactive oxygen species are also believed to be one of the causativefactors in neuronal death during the reperfusion phase after globalischemia. Ischemia-reperfusion injury caused by global or local ischemiaor during transplantation can also affect other major organs of the bodysuch as the kidney, liver and heart. Reactive oxygen intermediates thatare generated during the reperfusion phase in these organs are thoughtto cause significant injury.

Other degenerative diseases of the central nervous system are believedto be exacerbated or initiated by processes that result in thegeneration of reactive oxygen intermediates. Parkinson's disease (PD) ischaracterized by reduced size and velocity of movements. In Alzheimer'sdisease (AD), cognitive impairment is the cardinal clinical symptom. Inmotoreuron disease, (for example, amyotrophic lateral sclerosis, ALS), adegeneration of the central pyramidal, the peripheral motor system orboth is the reason for the clinical picture.

Idiopathic PD is a movement disorder in which symptomatology is definedby three cardinal symptoms: tremor at rest, rigidity and akinesia (Fahn,1989). The course of the disease is a progressive one. For a long time,anticholinergic drugs were the only effective treatment of parkinsoniansymptoms. The beneficial effect of L-3,4-dihydrophenylalanine (L-DOPA)therapy has increased patient's life expectancy to a significant degree.However, the advanced stage of the disease is dominated by thecomplications of L-DOPA therapy and lack of L-DOPA responsiveness. Alimiting factor in PD therapy is the psychotic potential of manyanti-parkinsonian drugs.

ALS is a chronic progressive degenerative disorder, which, in itsclassical form, appears sporadically. The most prominent pathologicalchange in ALS patients is a loss of large motoreurons in the motorcortex, brain stem and spinal cord.

Cognitive decline is the essential clinical criteria for AD manifestedby memory loss, disorientation and the concomitant loss of enjoyment oflife associated therewith. Only after death can the diagnosis beconfirmed pathologically by the presence of numerous amyloid andneuritic plaques in the brain.

At present, the pharmacological therapy of neurodegenerative disordersis limited to symptomatic treatments that do not alter the course of theunderlying disease.

Meanwhile, because of the current dissatisfaction with the currentlymarketed treatments for the above-described indications within theaffected population, the need continues for safer, better-calibrateddrugs which will either slow the process of neurodegeneration associatedwith focal or global ischemia, ALS, Alzheimer's and Parkinson's diseaseor even prevent such neurodegeneration altogether.

The present invention provides new phenyl oxazole and phenyl thiazolecompounds useful for treating neurodegeneration and reperfusion injuryof peripheral organs. The compounds of the invention inhibit theformation of reactive oxygen species in a mammal and are thereby usefulfor treating conditions and diseases which are believed to be induced byincreased free radical production such as global and cerebral ischemia,Parkinson's disease, Alzheimer's disease, Down's syndrome, ALS andischemia/reperfusion injury of peripheral organs.

Malamas, et al., U.S. Pat. No. 5,428,0478 disclose phenyl oxazolesuseful for treating diseases of inflammation, allergic responses andarteriosclerosis while Panetta, et al., EP Application No. 677,517 teachbenzylidene rhodanines to treat Alzheimer's disease.

SUMMARY OF THE INVENTION

This invention provides compounds of the formula III

wherein:

Ar is phenyl, pyridyl, tetrehydronaphthyl, benzofuranyl or chromanylsubstituted with zero to two substituents selected from the groupconsisting of —(C₁-C₆)alkyl, hydroxy and halo; and

substituted with either:

(i) one or two substituents selected from the group consisting of—O(CH₂)_(t)R⁶,

 and —(C₁-C₆ alkyl)R⁶; or

(ii) two substituents which when taken together with the carbon atoms towhich they are attached form a pyridyl or tetrahydropyridyl ring;

provided that when substituent pattern (i) is present, the phenyl orpyridyl group of Ar may additionally be substituted with twosubstituents which when taken together with the carbon atoms to whichthey are attached form a phenyl ring;

where R⁶ is —NR⁷R⁸, morpholin-1-yl, imidazol-1-yl,4,5-dihydro-1H-imidazol-2-yl, thiomorpholin-1-yl, piperazin-1-yl orpiperazin-1-yl substituted with —(C₁-C₄)alkyl or

and R⁷ and R⁸ are each individually hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(p)OH,

—(CH₂)_(p)-piperidyl, —(CH₂)_(p)S (C₁-C₆)alkyl, —(CH₂)_(p)O(C₁-C₆)alkyl

where R⁹ is (C₁-C₆)alkyl;

represents a double or single bond;

X is —O— or —S—;

Y is —CR⁵′R⁵—, —O— or —S—, where R⁵′ is H and R⁵ is —H or —OH or R5 andR⁵′ taken together are ═O;

Z is —CH₂— or —N—;

R is H or —(C₁-C₆)alkyl;

R¹ and R² are each individually —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy or phenyl;

R³ is H or —(C₁-C₆)alkyl or R³ and R⁴ taken together form a phenyl groupwith the ring to which they are attached;

R⁴ is hydrogen or —OH, or when Y is —CHR⁵, R⁴ and R⁵ are eachindividually H or when taken together form a bond;

m is an integer from 0 to 2, both inclusive;

q is 0 or 1;

n is an integer from 0 to 4 both inclusive;

p is an integer from 1 to 6 both inclusive; and

t is an integer from 1 to 4 both inclusive;

or a pharmaceutically acceptable salt, hydrate or optical isomerthereof.

According to a further aspect of the present invention there areprovided pharmaceutical compositions comprising as active ingredient acompound of formula III or a pharmaceutically acceptable salt, hydrateor optical isomer thereof, in association with one or morepharmaceutically acceptable diluents, carriers and excipients thereof.

The present invention in addition provides a method for inhibiting theformation of reactive oxygen species in a mammal which comprisesadministering to said mammal a therapeutically effective amount of acompound of the formula III.

The present invention also provides a method for inhibiting lipidperoxidation in a mammal in need of such treatment which comprisesadministering to said mammal a therapeutically effective amount of acompound of the formula III.

Moreover, it has been discovered that compounds of formula I are alsouseful for preventing ischemia-induced cell damage such as may be causedby strokes, myocardial infarction, cardiac arrest or duringtransplantation. Ischemia represents a phenomenon in which tissue isdeprived of either partial or total blood flow in conjunction withhypoxia. Reperfusion of such tissue causes additional tissue injuryassociated with ischemic events to vital organs such as the lung, liver,kidney, heart and small bowel. This invention, therefore, also providesa method for preventing ischemia-induced cell damage in mammals byadministering to a mammal in need thereof an therapeutically effectiveamount of a compound of formula III.

Further, the present invention provides a method for treatingParkinson's disease in a mammal in need of such treatment whichcomprises administering to said mammal a therapeutically effectiveamount of a compound of formula I.

In another aspect of the present invention is provided a method fortreating Alzheimer's disease in a mammal in need of such treatment whichcomprises administering to said mammal a therapeutically effectiveamount of a compound of formula III.

Still another aspect of the present invention provides a method oftreating amyotrophic lateral sclerosis (ALS) in a mammal in need of suchtreatment which comprises administering a therapeutically effectiveamount of a compound of formula III.

Other objects, features and advantages of the present invention willbecome apparent from the subsequent description and the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “C₁-C₆ alkyl” represents a straight or branchedalkyl chain having from one to six carbon atoms. Typical C₁-C₆ alkylgroups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, hexyl and the like.

The term “halo” means chloro, fluoro, bromo or iodo.

The term “(C₁-C₆)alkoxy” means a group such as methoxy, ethoxy,n-propoxy, isopropxy, n-butoxy, t-butoxy, n-pentoxy, isopentoxy,neopentoxy, hexoxy and like groups attached to the remainder of themolecule by the oxygen atom.

The term “pharmaceutically acceptable salts” refers to salts of thecompounds of the above formulae which are substantially non-toxic toliving organisms. Typical pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the above formulaewith a pharmaceutically acceptable mineral or organic acid, or apharmaceutically acceptable alkali metal or organic base, depending onthe types of substituents present on the compounds of the formulae.

Examples of pharmaceutically acceptable mineral acids which may be usedto prepare pharmaceutically acceptable salts include hydrochloric acid,phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid,phosphorous acid and the like. Examples of pharmaceutically acceptableorganic acids which may be used to prepare pharmaceutically acceptablesalts include aliphatic mono and dicarboxylic acids, such as oxalicacid, carbonic acid, citric acid, succinic acid, phenyl-substitutedalkanoic acids, aliphatic and aromatic sulfuric acids and the like. Suchpharmaceutically acceptable salts prepared from mineral or organic acidsthus include hydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate,bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, hydroiodide,hydrofluoride, acetate, propionate, formate, oxalate, citrate, lactate,p-toluenesulfonate, methanesulfonate, maleate, and the like.

It should be recognized that the particular anion or cation forming apart of any salt of this invention is not critical, so long as the salt,as a whole, is pharmacologically acceptable and as long as the anion orcationic moiety does not contribute undesired qualities.

The term “amino-protecting group” is used herein as it is frequentlyused in synthetic organic chemistry, to refer to a group which willprevent an amino group from participating in a reaction carried out onsome other functional group of the molecule, but which can be removedfrom the amine when it is desired to do so. In a similar fashion, theterm “hydroxy protecting group” refers to a removable group which willprevent a hydroxy group from participating in a reaction performed onthe molecule. Such groups are discussed by T. W. Greene in chapters 2and 7 of Protective Groups in Organic Synthesis, John Wiley and Sons,New York, 1981, and by J. W. Barton in chapter 2 of Protective Groups inOrganic Chemistry, J. F. W. McOmie, ed., Plenum Press, New York, 1973,which are incorporated herein by reference in their entirety. Examplesof amino protecting groups include benzyl and substituted benzyl such as3,4-dimethoxybenzyl, o-nitrobenzyl, and triphenylmethyl; those of theformula —COOR where R includes such groups as methyl, ethyl, propyl,isopropyl, 2,2,2-trichloroethyl, 1-methyl-1-phenylethyl, isobutyl,t-utyl, t-amyl, vinyl, allyl, phenyl, benzyl, p-nitrobenzyl,o-nitrobenzyl, and 2,4-dichlorobenzyl; acyl groups and substituted acylsuch as formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl,trifluoroacetyl, benzoyl, and p-methoxybenzoyl; and other groups such asmethanesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl,p-nitrophenylethyl, and p-toluenesulfonylaminocarbonyl. A preferredamino-blocking group is t-butoxycarbonyl.

Examples of hydroxy protecting groups include ether and substitutedether forming groups such as methyl, methoxymethyl, t-butoxymethyl,1-ethoxyethyl and benzyl; silyl ether forming groups such astrimethylsilyl, triethylsilyl and methyl-diisopropylsilyl; ester forminggroups such as formate, acetate and trichloroacetate and carbonategroups, such as methyl, 2,2,2-trichloroethylcarbonate and p-nitrophenylcarbonates.

The compounds of the instant invention may exist in various isomericforms, for example, when Ar is a phenyl or pyridyl substituted with oneor two —(C₁-C₆ alkyl)R⁶ groups or when R⁴ and R⁵ taken together form abond or when Y is —C(OH)H—. This invention is not related to anyparticular isomer but includes all possible individual isomers andracemates.

The skilled artisan will understand that when Z is nitrogen and

is a double bond between Z and the carbon to which it is attached, N hasno R³ substituent.

Many of the compounds of formula I can combine with water to formhydrates. This invention encompasses the hydrates of formula I.

PREFERRED COMPOUNDS OF THE INVENTION

Preferred groups include the following:

(a) Ar is phenyl substituted with one or two substituents selected from

and —(C₁-C₆ alkyl)R⁶ or with two substituents which when taken togetherwith the carbon atoms to which they are attached form a pyridyl ortetrahydropyridyl ring;

(b) Ar is phenyl substituted with —(C₁-C₆)alkyl, hydroxy, halo or withtwo substituents which when taken together with the carbon atoms towhich they are attached form a phenyl ring;

(c) Ar is pyridyl substituted with —(C₁-C₆)alkyl, hydroxy, halo or withtwo substituents which when taken together with the carbon atoms towhich they are attached form a phenyl ring;

(d) Ar is phenyl substituted with —(C₁-C₆ alkyl)R⁶;

(e) Ar is phenyl substituted with

(f) R⁶ is —NR⁷R⁸;

(g) R⁶ is morpholin-1-yl or thiomorpholin-1-yl;

(h) R⁶ is imidazol-1-yl or 4,5-dihydro-1-1H-imidazol-2-yl;

(i) R⁶ is piperazin-1-yl or piperazin-1-yl substituted with—(C₁-C₄)alkyl or

(j) R⁷ and R⁸ are each individually hydrogen or —(C₁-C₆)alkyl;

(k) R¹ and R² are each individually —(C₁-C₆)alkyl;

(l) R³ is —(C₁-C₆)alkyl;

(m) Y is —O— or —S—;

(n) Y is —CHR⁵—;

(o) m is 1;

(p) p is an integer from 1-3 both inclusive.

A preferred group of compounds include compounds of the formula (II)

wherein:

Ar is phenyl, pyridyl, or tetrahydronaphthyl substituted with zero totwo substituents selected from the group consisting of —(C₁-C₆)alkyl,hydroxy and halo; and

substituted with either:

(i) one or two substituents selected from the group consisting of—O(CH₂)_(t)R⁶,

 and —(C₁-C₆ alkyl)R⁶; or

(ii) two substituents which when taken together with the carbon atoms towhich they are attached form a pyridyl or tetrahydropyridyl ring;

provided that when substituent pattern (i) is present, the phenyl orpyridyl group of Ar may additionally be substituted with twosubstituents which when taken together with the carbon atoms to whichthey are attached form a phenyl ring;

where R⁶ is —NR⁷R⁸, morpholin-1-yl, imidazol-1-yl,4,5-dihydro-1H-imidazol-2-yl, thiomorpholin-1-yl, piperazin-1-yl orpiperazin-1-yl substituted with —(C₁-C₄)alkyl or

and R⁷ and R⁸ are each individually hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(p)OH, —(CH₂)_(p)-piperidyl, —(CH₂)_(p)S(C₁-C₆)alkyl or

represents a double or single bond;

X is —O— or —S—;

Y is —CHR⁵—, —O— or —S—;

Z is —CH— or —N—;

R is H or —(C₁-C₆)alkyl;

R¹ and R² are each individually —(C₁-C₆)alkyl or —(C₁-C₆)alkoxy;

R³ is H or —(C₁-C₆)alkyl, or R³ and R⁴ taken together form a phenylgroup with the ring to which they are attached;

R⁴ is hydrogen, or when Y is —CHR⁵, R⁴ and R⁵ are each individually H orwhen taken together form a bond;

m is an integer from 0 to 2, both inclusive;

q is 0 or 1;

n is an integer from 0 to 4 both inclusive;

p is an integer from 1 to 6 both inclusive; and

t is an integer from 1 to 4 both inclusive;

or a pharmaceutically acceptable salt, hydrate or optical isomerthereof.

Another preferred group of compounds include compounds of the formula(I)

wherein:

Ar is phenyl or pyridyl substituted with zero to two substituentsselected from the group consisting of —C₁-C₆ alkyl, hydroxy and halo;and

substituted with either:

(i) one or two substituents selected from the group consisting of

 and —(C₁-C₆ alkyl)R⁶; or

(ii) two substituents which when taken together with the carbon atoms towhich they are attached form a pyridyl or tetrahydropyridyl ring;

provided that when substituent pattern (i) is present, the phenyl orpyridyl croup of Ar may additionally be substituted with twosubstituents which when taken together with the carbon atoms to whichthey are attached form a phenyl ring;

where R⁶ is —NR⁷R⁸, morpholin-1-yl, imidazol-1-yl,4,5-dihydro-1H-imidazol-2-yl, thiomorpholin-1-yl, piperazin-1-yl orpiperazin-1-yl substituted with —(C₁-C₄)alkyl or

and R⁷ and R⁸ are each individually hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(p)OH or —(CH₂)_(p)-piperidyl;

X is —O— or —S—;

Y is —CHR⁵—, —O— or —S—;

R is —H or (C₁-C₆)alkyl;

R¹ and R² are each individually —(C₁-C₆)alkyl;

R³ is H or —(C₁-C₆)alkyl;

R⁴ is hydrogen, or when Y is —CHR⁵, R⁴ and R⁵ are each individually H orwhen taken together form a bond;

m is 0 or 1;

n is an integer from 0 to 4 both inclusive; and

p is an integer from 1 to 6 both inclusive;

or a pharmaceutically acceptable salt, hydrate or optical isomerthereof.

It will be understood that the above classes may be combined to formadditional preferred classes.

A preferred genus of compounds include those compounds where:

Ar is phenyl substituted with one or two substituents selected from

and —(C₁-C₆ alkyl)R⁶ where R⁶ is —NR⁷R⁸ and R⁷ and R⁸ are H or—(C₁-C₆)alkyl;

and one or two substituents selected from hydrogen, —(C₁-C₆)alkyl andhydroxy; or two substituents which when taken together with the carbonatoms to which they are attached form a phenyl group.

R¹ and R² are —(C₁-C₆)alkyl;

R, R³ and R⁴ are hydrogen;

X is —O—;

Y is —O— or —S—;

Of this preferred genus, compounds in which R¹ and R² are1,1-dimethylethyl are more preferred.

Of this more preferred genus, those compounds in which Ar is phenylsubstituted with one or two —(C₁-C₆ alkyl)R⁶ groups and one or twosubstituents selected from hydrogen and —(C₁-C₆)alkyl are especiallypreferred.

Of this especially preferred genus, those compounds in which Ar isphenyl substituted with —(C₁-C₆ alkyl)R⁶ are particularly preferred.

Further typical examples of compounds of formula I which are useful inthe present invention include:

2-(3-methyl-4-hydroxy-5-ethyl)phenyl-4-(2-(4-methyl-3-aminoprop-1-ylphenoxy)ethyl)oxazole

2-(3-isopropyl-4-ethoxy-5-n-propyl)phenyl-4-(2-(4-N-propyl-6-aminohex-1-ylphenoxy)ethyl)thiazoleoxalate

2-(3-hexyl-4-pentoxy-5-t-butyl)phenyl-4-(2-(4-N-ethylaminomethylphenoxy)ethyl)oxazole

2-(3-n-propyl-4-hydroxy-5-neopentyl)phenyl-4-(2-(4-N-ethylaminomethylphenoxy)ethyl)-5-methyloxazolemaleate

2-(3-isopropyl-4-propoxy-5-ethyl)phenyl-4-(2-(4-N-ethylaminomethylphenoxy)ethyl)-5-ethylthiazole

2-(3-methyl-4-n-pentoxy-5-sec-butyl)phenyl-4-(2-(4-N-ethylaminomethylphenoxy)ethyl)-5-isopropyloxazoletosylate

2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-ethylaminomethylphenoxy)ethyl)thiazole

2-(3-methyl-4-methoxy-5-n-butyl)phenyl-4-(2-(2-fluoro-4-N-ethylaminomethylphenoxy)ethyl)oxazolehydrobromide

2-(3-t-butyl-4-hydroxy-5-ethyl)phenyl-4-(2-(2-propyl-4-N-ethylaminomethylphenoxy)ethyl)oxazole

2-(3-isobutyl-4-hydroxy-5-n-pentyl)phenyl-4-(2-(4-N-ethylaminomethyl-5-hydroxyphenoxy)ethyl)thiazole

2-(3,5-dimethyl-4-ethoxyphenyl)-4-(2-(2-hexyl-4-N-ethylaminomethylphenoxy)ethyl)oxazolemesylate

2-(3-n-butyl-4-pentoxy-5-isopropylphenyl)-4-(2-(5-N-ethyl-N-methylaminomethylpyrid-2-yloxy)ethyl)thiazole

2-(3-neopentyl-4-hydroxy-5-ethylphenyl)-4-(2-(5-N-ethyl-N-methylaminomethylpyrid-2-yloxy)ethyl)-5-methyloxazolenitrate

2-(3,5-di-sec-butyl-4-hydroxyphenyl)-4-(2-(5-N-ethyl-N-methylaminomethylpyrid-2-yloxy)ethyl)-5-isobutyloxazole

2-(3,5-di-n-propyl-4-methoxyphenyl)-4-(2-(5-N-ethyl-N-methylaminomethylpyrid-2-yloxy)ethyl)oxazolepyrosulfate

2-(3-sec-butyl-4-methoxy-5-ethyl)phenyl-4-(2-(2-bromo-5-N-ethyl-N-methylaminomethylpyrid-2-yloxy)ethyl)-5-isopropyloxazole

2-(3,5-di-isopropyl-4-hydroxyphenyl)-4-(2-(3-hydroxy-5-thiomorpholinomethylpryid-2-yloxy)ethyl)thiazolemetaphosphate

2-(3-methyl-4-propoxy-5-ethyl)phenyl-4-(2-(5-N-methyl-N-ethyl-4-aminobut-1-ylpyrid-2-yloxy)ethyl)oxazole

2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(5-(N-methyl-N-(3-(piperidin-3-yl)propyl)aminomethyl)pyrid-2-yloxy)ethyl)oxazolemethanesulfonate

2-(3,5-di-t-butyl-4-methoxyphenyl)-4-(2-(5-N-ethyl-N-methyl-3-aminopropyl-1-yl-pyrid-2-yloxy)ethyl)oxazolesulfate

2-(3,5-di-t-butyl-4-ethoxyphenyl)-4-(2-(5-N-ethyl-N-n-propylaminomethylpyrid-2-yloxy)ethyl)thiazole

2-(3-hexyl-4-ethoxy-5-ethylphenyl-4-(2-(4-N-methyl-N-n-butylaminomethylphenylthio)ethyl)oxazolephosphate

2-(3-n-propyl-4-methoxy-5-hexylphenyl)-4-(2-(4-N-methyl-N-ethylaminomethylphenylthio)ethyl)thiazole

2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-chloro-4-N,N-dimethylaminomethylphenylthio)ethyl)-5-isopropyloxazolecitrate

2-(3-t-butyl-4-hydroxy-5-neopentyl)phenyl-4-(2-(3,5-dimethyl-4-N,N-diethyl-3-aminopropyl-1-ylphenylthio)ethyl)oxazole

2-(3,5-dimethyl-4-hydroxyphenyl)-4-(2-(4-(N-methyl-N-3-(piperin-3-yl)prop-1-yl-2-aminomethyl-1-ylphenylthio)ethyl)oxazolebisulfate

2-(3-methyl-4-hydroxy-5-ethyl)phenyl-4-(2-(4-N-n-propyl-N-ethylaminomethylphenylthio)ethyl)thiazole

2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethylphenyl)ethyl)-5-methylthiazolelactate

Z-2-(3,5-di-t-butyl-4-propoxyphenyl)-4-(3-(4-N-N-di-n-butylaminomethylphenyl)-2-propenyl)oxazole

E-2-(3-methyl-5-n-butyl-4-ethoxyphenyl)-4-(4-(4-methylethylaminomethylpyridyl)ethyl)oxazole

2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethylphenyl)oxazole

Z-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethylphenyl)-2-propenyl)oxazole

E-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethylphenyl)-2-propenyl)oxazole

Synthesis Methods

The compounds of formula I where Ar is phenyl substituted with one ortwo —(C₁-C₆ alkyl)R⁶ groups where the alkyl group is —CH₂—, X and Y areoxygen, R⁴ is hydrogen and m is 1 are prepared according to thefollowing general reaction scheme I(a)(1).

In step (a) of the above reaction scheme, an appropriately substitutedbenzoic acid is converted to the benzamide (1) by refluxing with anactivating agent such as 2-chloro-4,6-dimethoxy-1,3,5-trizine (CDMT)1,1′-carbonyldiimidazole (CDI), or dicyclohexylcarbodiimide (DCC),preferably CDMT, then cooling to ambient temperature and treating withconcentrated aqueous ammonia or an ammonia equivalent such ashexamethyldisilazine. The reaction can be conducted in an aprotic polarsolvent, preferably tetrahydrofuran, for a period of from 1 to 24 hours.

The oxazoleacetic acid compound (2) is prepared in step (b) by cyclizingthe benzamide (1) with a reagent such as ethyl-4-chloroacetoacetatepreferably neat under an inert gas such as nitrogen at a temperature ofabout 50° C. to 130° C., preferably at 130° C., for about one to twohours and then hydrolysing to form the acid which may be isolated byrecrystalization, if desired. Optionally, solvents such as xylene ortoluene may be employed and the reaction run at reflux temperatures.

Preparation of the phenyloxazole (3) is achieved in step (c) by reducingthe acid (2) with a reducing agent, preferably an excess of boranetetrahydrofuran, followed by treatment with an alcoholic or proticsolvent, preferably methanol. Other suitable reducing agents includeborane 4,6-dimethyoxybenzene-1,3-disulfonyl chloride, lithium aluminumhydride, sodium borohydride or lithium borohydride. The reaction can beconducted in an aprotic polar solvent such as tetrahydrofuran, ordioxane, preferably tetrahydrofuran, at temperatures from about −10° C.to ambient temperature, preferably ambient temperature for about 1 to 24hours.

In step (d), the phenyloxazole (3) can be coupled with a hydroxysubstituted benzaldehyde to form aldehyde (4) by first mesylating (3)with a mesylating agent such as methanesulfonyl chloride and thencoupling the mesylated compound with the benzaldehyde. The couplingreaction can be conducted in an aprotic polar solvent such asdimethylsulfoxide in the presence of potassium t-butoxide while heatingto a temperature of about 70° C. for up to 24 hours.

When R¹ and R² are small lower alkyl substituents such as methyl orethyl, the hydroxy of the phenyl ring is preferably protected with ahydroxy protecting group to prevent mesylation of the phenol. Theprotecting group may then be removed after the coupling step.

When R¹ and R² are bulky alkyl substituents such as t-butyl, mesylationpreferentially occurs on the alcohol attached to the oxazole or thiazolering, thus the hydroxy does not need to be protected.

Alternately, preparation of (4) can be accomplished by a Mitsunobucoupling which can be conducted in an aprotic polar solvent, such astetrahydrofuran, at ambient temperature.

Reductive amination of the aldehyde to form desired product (5) isaccomplished in step (e) by reacting compound (4) with an appropriatelysubstituted amine and titanium IV isopropoxide (Ti(OiPr)₄) using areducing agent such as sodium borohydride. The reaction is preferablyconducted at ambient temperature in a low molecular weight alcohol suchas ethanol. The reaction is substantially complete in 16 hours to 3days.

Alternately, the reduction step (e) can be accomplished by dissolvingthe aldehyde (4) in a low molecular weight alcohol, such as methanol,acidifying the solution with an excess of an organic acid, such asacetic acid, then reacting the aldehyde (4) with an appropriatelysubstituted amine using a reducing agent, such as sodiumcyanoborohydride (sodium cyanoborohydride). The reaction is conducted atambient temperatures under an inert gas, such as nitrogen, and thereaction is substantially complete in about six hours. Abdel-Maged, etal., J. Org. Chem., 1996, 61, 3849.

Similarly, the reductive amination reaction can be accomplished indichloroethane using sodium (triacetoxy)borohydride.

Compounds of Formula I where R is —(C₁-C₆)alkyl can be prepared byalkylating the phenol of compound (4) of Scheme I(a), after the couplingstep (d), using an appropriate —(C₁-C₆)alkyl halide, such as methyliodide, and sodium hydride in an aprotic polar solvent or solventmixture such as tetrahydrofuran and dimethylformamide. The reaction maybe conducted at ambient temperature and is substantially complete within31 hours. Reductive amination can then be accomplished as described inScheme I(a), step (e).

In an alternate procedure as depicted in Scheme I(a)(2), below, thephenyl oxazole (3) is treated with a mesylating agent, preferablymethanesulfonyl chloride in the presence of a base, preferablytriethylamine. Other suitable bases include pyridine or 2,6-lutidene ordiisopropyl ethylamine. The reaction is preferably conducted under aninert atmosphere, such as nitrogen, using an aprotic solvent, preferablymethylene chloride. Tetrahydrofuran or acetonitrile are otherappropriate solvents. At temperatures of from −10° C. to ambienttemperatures, preferably at about 0° C., the reaction is substantiallycomplete in 1 to 24 hours.

In a preferred procedure, the phenol oxazole (3) is treated with atosylating agent such as tosyl chloride or, preferably, tosic anhydride,in the presence of a base, preferably pyridine and a catalyst such asdimethylaminopyridine. Other tertiary amines such as triethylamine, or2,6-lutidine may also be employed. The reaction is preferably conductedunder an inert gas, such as nitrogen at temperatures of from about −10°C. to 35° C., preferably at ambient temperatures. Aprotic solvents, suchas tetrahydrofuran or methylene chloride, are preferred.

Desired product (5) may then be readily accomplished by refluxing themesylate or tosylate (110) with amine (111) in the presence of a strongbase, preferably sodium hydride or sodium t-butoxide. Potassium basesare also acceptable but less preferred than sodium. Suitable solventsinclude but are not limited to aprotic solvents such as tetrahydrofuran,dimethylsulfoxide, dimethylformamide or dioxane.

In a preferred one-pot alkylation, the tosylate (110) and amine (111)are refluxed under an inert gas such as nitrogen in the presence ofanhydrous solid sodium hydroxide as a bare using tetrahydrofuran as asolvent.

Where t is 1, amine (111) is prepared according to the procedures ofAbdel-Maged, et al., supra.

Alternately, where t is 1-6, preparation of (11) is accomplished asshown in Scheme I(a)(3), below.

A solution of carboxylic acid (115) in an aprotic solvent such astetrahydrofuran is treated with an activating group, preferablyisobutylchloroformate in the presence of a base such as4-methyl-morpholine. Other suitable activating agents include arylalkylchloroformates, such as phenyl. The reaction is conducted attemperatures of from about −78° C. to ambient temperature, preferably atabout −50° C.

An amine of the formula HNR⁷R⁸ is added and the reaction is allowed toproceed, preferably at temperatures of about −50° C. Reduction of theamide (116) to amine (111) is then readily achieved using a reducingagent, such as borane dimethylsulfide.

Compounds of Formula I where R⁷ or R⁸ are —(CH₂)_(p)piperidyl,—(CH₂)_(p)S(C₁-C₆)alkyl or

can be prepared as shown in Scheme I(b) below, by reacting the aldehyde(4) with an amine or an amine hydrochloride salt of the formula H₂NR¹⁰where R¹⁰ is H or —(C₁-C₆)alkyl, to form the free amine (6), which canthen be alkylated with an alkylating agent such as amino-protectedpiperidine, for example,N-tert-butoxycarbonyl-3-(3-bromopropyl)piperidine or with 2-chloroethylmethyl sulfide using sodium hydride in an aprotic polar solventsuch as dimethylformamide to form (7). Temperatures of from about 20° C.to 80° C. are preferred and the reaction is substantially completewithin 4 hours. Deprotection of the piperidyl group may be accomplishedby techniques familiar to the skilled artisan such as by treatment of(7) with an acid such as hydrochloric acid. Conversion to the sulfoxidecan be achieved by treatment with an oxidizing agent, such asm-chloroperbenzoic acid.

Compounds of formula I where Ar is phenyl substituted with one or twostraight chain —(C₂-C₆ alkyl)R⁶ groups and X, Y and R⁴ are as defined inScheme I(a) above can be prepared as described in Schemes I(c-e) below.

In Scheme I(c), an amino-substituted phenol starting material (8) isreacted with an acylating agent such as acetic anhydride and sodiummethoxide in a low molecular weight alcohol, such as methanol, to formcompound (9). Reduction of the carbonyl can be achieved with a reducingagent, such as lithium aluminum hydride in an aprotic solvent, such astetrahydrofuran, to produce compound (10). Acylation of (10) can beaccomplished by reacting 1,1-carbonyldiimidazole with a carboxylic acidin an aprotic polar solvent such as tetrahydrofuran at temperatures offrom about 0° C. to about 20° C., then treating withN-ethyl-p-hydroxyphenethyl amine (10). The reaction is substantiallycomplete in 2 to 24 hours.

Compound (11) can then be coupled with an appropriately substitutedphenyloxazole in a Mitsunobu reaction to prepare (12). The reaction canbe conducted in a polar aprotic solvent such as tetrahydrofuran atambient temperature. After approximately 24 hours, the reaction issubstantially complete. Compound (12) can then be reduced using areducing agent, such as aluminum hydride in an aprotic solvent, such astetrahydrofuran, to prepare (13). The reaction is appropriatelyconducted at ambient temperatures and is complete in about three hours.

In an alternate procedure, as shown in Scheme I(d) below, anappropriately substituted phenylalkanol starting material (14),dissolved in an organic solvent such as methylene chloride, is reactedwith a halogenating agent such as dibromotriphenylphosphorane to preparecompound (15). The reaction may be conducted at ambient temperature andallowed to proceed for about four hours.

The halogenated compound (15) is then coupled with an appropriatelysubstituted phenyl oxazole in a Mitsunobu reaction to prepare (16)followed by displacement of the halogen with an amine of the formula—NR⁷R⁸ in a polar aprotic solvent such as dimethylformamide at about 80°C. for about five hours to prepare the desired final product.

Scheme I(e) below describes a third procedure for preparing compounds offormula I where Ar is phenyl substituted with one or two straight chain—(C₂-C₆ alkyl)R⁶ groups.

In a Mitsunobu reaction, compound (17) is first coupled with anappropriately substituted phenyl oxazole to form the intermediateoxazole (18). Reduction of the cyano group followed by hydrolysisprepares compound (19). Amination of compound (19) is achieved by eithermethod described in Scheme I(a), step (e).

Compounds of formula I where Ar is phenyl substituted with one or two

groups, and X and Y are as defined in Scheme I(a-e) above can beprepared as outlined in Scheme II below.

In the above reaction Scheme II, an appropriately substituted phenyloxazole (20), dissolved in an aprotic polar solvent such astetrahydrofuran, is coupled with an appropriately substituted phenol(21) in a Mitsunobu reaction to form (22). At ambient temperatures, thereaction is substantially complete in 5 hours. Compound (22) is thentreated with sodium iodide to form the iodoketone which is thendisplaced using an appropriately substituted amine while heating toabout 50° C.-80° C. The amination can be conducted in a non-polarorganic solvent such as toluene and is substantially complete in aboutthree hours.

Compounds of formula I where Ar is phenyl substituted with one or twobranched —(C₁-C₆ alkyl)R⁶ groups, and X and Y are as described in SchemeI(a-e) above can be prepared according to Scheme III below.

An appropriately substituted phenyloxazole (24), dissolved in an aproticpolar solvent such as tetrahydrofuran, is coupled with an appropriatelysubstituted ketone (25) in a Mitsunobu reaction to form compound (26).Reductive amination of (26) can be achieved by either of the methodsdescribed in Scheme I(a), step (e).

Compounds of Schemes I, II or III wherein Ar is phenyl additionallysubstituted with one or two substituents selected from —(C₁-C₆)alkyl,halo and hydroxy can be prepared as shown in Scheme IV below.

An appropriately substituted phenyl oxazole and appropriatelysubstituted phenol (27) are coupled in a Mitsunobu reaction as describedin Scheme I(a), step (d), to form the intermediate compound (28) whichcan then be aminated using either of the two methods described in SchemeI(a), step (e). The hydroxy may then be deprotected where appropriate.

Compounds of Schemes I, II or III where Ar is phenyl substituted withtwo substituents which, when taken together, form a phenyl ring can beprepared as shown in Scheme V below.

Using a Mitsunobu coupling, a phenyloxazole starting material is reactedwith an appropriately substituted hydroxynaphthaldehyde (29). Theresulting product can then be subjected to reductive amination usingeither method of Scheme I, step (e) and the hydroxy deprotected whereappropriate.

Compounds of Schemes I, II or III where Ar is phenyl substituted with

and/or —(C₁-C₆ alkyl)R⁶; where R⁶ is morpholin-1-yl, piperazin-1-yl,thiomorpholin-1-yl or substituted piperazin-1-yl are prepared accordingto reaction Scheme VI.

where B is —O—, —NH—,

—N(C₁-C₄ alkyl) or —S—, R^(a) is oxo-substituted —(C₁-C₆)alkyl and R^(b)is —(C₁-C₆)alkyl.

An appropriately substituted starting material (30) is coupled byreductive amination with an appropriately substituted phenyloxazoleaccording to the reactions of Scheme I(a), Step (e), i.e., using eithera reducing agent such as sodium cyanoborohydride in an aprotic polarsolvent such as tetrahydrofuran, or titanium IV isopropoxide (Ti(OiPr)₄)and sodium borohydride in a low molecular weight alcohol such as ethanolto form (31).

Compounds of Formula I where R⁶ is piperazin-1-yl can be prepared bytreating compound (31) of Scheme VI, where B is

with an excess of an inorganic acid such as hydrochloric acid.

Compounds of formula I where R⁶ is imidazol-1-yl are prepared accordingto the following Scheme VII.

A methoxyphenylalkylhalide such as p-methoxybenzyl chloride is refluxedwith imidazole to form (32). The reaction, conducted in a polar organicsolvent such as acetonitrile, is substantially complete in about 16hours. Demethylation of (32) is achieved by treatment with an agent,such as boron tribromide, to form compound (33). In a Mitsunobucoupling, compound (33) can be coupled with the phenyloxazole (34) toform the desired product (35).

Compounds of formula I where R⁶ is 4,5-dihydro-1-H-imidazol-2-yl areprepared according to Scheme VIII.

A phenyloxazole starting material is coupled with a hydroxyphenylalkylcyanide compound in a Mitsunobu reaction. Cyclization of the cyano groupto form the dihydroimidazole (37) can be achieved by first, treating(36) with hydrogen chloride gas in ethanol at low temperatures for aboutfour hours then refluxing with ethylenediamine for an additional periodof up to 32 hours.

Compounds of formula I where Ar is phenyl substituted with twosubstituents which when taken together with the carbons to which theyare attached form a pyridyl or tetrahydropyridyl can be preparedaccording to Schemes IX(a) and IX(b) below.

In the above reaction Schemes IX(a) and IX(b), starting material (38) iscyclized with the appropriate aldehyde in an acid solution to formintermediate (39) as an oxalate salt.

In Scheme IX(a), intermediate (39) can first be demethylated byrefluxing the oxalate salt (38) with hydrogen bromide then protectingthe nitrogen with an amino-protecting agent such as di-tert-butyldicarbonate to prepare (40).

In Scheme IX(b), the free amine (39) can be aromatized in the presenceof dehydrogenating reagent by heating with palladium black followed bydemethylation, as discussed above, to form (42).

Compounds (40) or (42) can then be coupled with an appropriatelysubstituted phenyloxazole in a Mitsunobu reaction, to form the desiredproducts (41) or (43). Removal of the nitrogen protecting group can beachieved by standard methodology such as by treatment withtrifluoroacetic acid and an appropriate t-butyl cation scavenger such asthiophenol. If a hydroxy protecting group is employed, the hydroxy groupmay be deprotected by, for example, hydrolysis or treatment with an aciddepending on the protecting group selected.

Compounds where Ar is substituted pyridyl can be achieved by thefollowing general reaction Scheme X

Using an appropriately substituted pyridone carboxaldehyde and anappropriately substituted phenyloxazole in a Mitsunobu couplingreaction, compound (44) is prepared. When R^(f) is a protected hydroxygroup, it may be deprotected after the coupling step. Compound (44) canthen undergo reductive amination using either process described inScheme I(a), step (e) above.

Compounds of formula I where Y is sulfur can be prepared as illustratedin Scheme XI below.

An appropriately substituted phenyloxazole is coupled with anappropriately substituted mercaptobenzaldehyde (45) in a Mitsunobureaction. The resultant intermediate (46) can then be reduced to thedesired amine using either of the reductive amination reactionsdescribed in Scheme I(a), step (e).

Compounds of formula I where R³ is —(C₁-C₆)alkyl and R, R¹, R², R⁴, Xand Y are as described above can be prepared as follows:

Potassium ethyl malonate is stirred with a metal halide, such asmagnesium chloride and a base, such as triethylamine, in an aproticpolar solvent such as acetonitrile under an inert gas such as nitrogenat ambient temperatures then reacted with an acid halide such asμ-chloro-propionyl chloride to form starting halide (47).

Intermediate (48) is formed by reacting the halide (47) with anappropriately substituted benzamide (1). prepared as described in SchemeI(a) above. The reaction is allowed to proceed at temperatures of about100° to 150° C. under an inert gas such as nitrogen for about 1 to 8hours.

Reduction of intermediate (48) with a reducing agent such as lithiumaluminum hydride affords compound (49). The reduction is conducted underan inert gas such as nitrogen in an aprotic polar solvent or ether suchas tetrahydrofuran for a period of from 1-24 hours.

Using a Mitsunobu coupling, an appropriately substituted benzaldehyde iscombined with intermediate (49) to form compound (50) which can then bereduced by reductive amination as described in Scheme I(a), step e,above to form the desired product.

Compounds of formula I where X is S can be prepared as follows:

Benzamide (52) is prepared by refluxing an appropriately substitutedbenzoic acid with an activating agent such as carbonyldiimidazole underan inert gas such as nitrogen, then reacting with methylamine asdescribed in Scheme I, Step (a) above. Using an aprotic polar solventsuch as tetrahydrofuran, the reaction is substantially complete in about2-24 hours.

Conversion to the thiobenzamide (53) is achieved by reacting (52) withLawessens reagent at temperatures of from 80° C. to 120° C. in anorganic solvent such as hexamethylphosphoramide under an inert gas suchas nitrogen for about 1 to 2 hours.

The synthesis of intermediate (55) is accomplished by refluxing thethioamide (53) under an inert gas such as nitrogen with an μ-haloketonesuch as ethyl 4-chloroacetoacetate in the presence of potassium iodide.An aprotic polar solvent or ether such as tetrahydrofuran is preferredend the reaction is complete within 1 to 6 hours.

Cyclization to prepare the thiazole (56) is achieved by reactingthioester (55) with an excess of ammonium acetate in acid such as aceticacid under an inert gas such as nitrogen for from 1 to 5 hours.

Reduction of the thiazole ester (56) is accomplished with a reducingagent such as lithium aluminum hydride. The reduction is preferablyconducted under an inert gas such as nitrogen in an aprotic polarsolvent such as tetrahydrofuran. The reaction is substantially completein 1 to 2 hours.

Using a Mitsunobu reaction, the thiazole intermediate (57) can becoupled with an appropriately substituted benzaldehyde to form (58)which can be isolated and purified and reduced to the desired amine byreductive amination as described in Scheme I(a), step (e) above.

Compounds of formula I where Y is CHR⁵, where R⁴ and R⁵ are individuallyhydrogen or R⁴ and R⁵ taken together form a bond can be preparedaccording to Scheme XIV as follows.

At ambient temperature, in a polar solvent such as methylene chloride,an appropriately substituted starting alcohol (59) is halogenated bytreatment with a halogenating agent such as triphenylphosphine andbromine in the presence of a base or acid scavenger such as imidazole.The reaction is substantially complete in 1-24 hours.

In a displacement reaction, the halogenated compound (60) is refluxedwith triphenylphosphine in a nonpolar solvent such as xylene for about24 hours to form the activated intermediate (61).

Intermediate (62) is prepared in a Wittig reaction using a strong basesuch as sodium hexamethyldisilazane and an appropriately protectedaldehyde such as terephthalaldehyde mono-(diethylacetal). The reactionis preferably conducted in an aprotic polar solvent such astetrahydrofuran at temperatures of from about −20° C. to about 0° C. andis substantially complete in about 3 to 10 hours.

It will be readily appreciated by the skilled artisan that intermediate(62) forms the E and Z isomers which may be readily separated byconventional chromatographic techniques.

The desired aldehyde (63) may then be deprotected by treatment with anaqueous acid such as hydrochloric acid for about 24 hours. Deprotectionis preferably conducted in a polar solvent or ether such as diethyletherat ambient temperature.

Reductive amination can be accomplished using either of the proceduresdescribed in Scheme I(a), Step (e).

Compounds of formula I where Y is —CHR⁵ and R⁵ is hydrogen can beprepared by hydrogenation of compound (64) with hydrogen gas and 5%palladium on carbon. The reduction is preferably conducted in anon-polar solvent such as toluene at ambient temperatures and issubstantially complete in about four hours.

Compounds of formula I where Ar, X and Y and R⁴ are as defined as inScheme I(a) above, and m=0 can be prepared as demonstrated in Scheme XVbelow.

Starting material (66) is achieved by treating an appropriatelysubstituted benzoic acid with a peptide coupling reagent, such as CDI,DCC or, preferably, CDMT, to form an activated acylating agent. Thereaction is preferably conducted in an aprotic solvent, such asmethylene chloride, at temperatures of from about −5° C. to ambienttemperature, preferably ambient temperatures. The activated intermediateis then reacted with an appropriately substituted serine compoundpreferably d,l-serine methyl ester. The reaction is conducted attemperatures from −20° C. to ambient temperature, preferably at about−10° C.

The methyl ester (66) may be cyclyzed to the oxazoline (67) by reactingwith a brominating agent, such as triphenylphosphine, and carbontetrabromide in the presence of a base. The reaction is conducted in anaprotic polar solvent, such as acetonitrile, at ambient temperature forfrom about 1 to 24 hours.

Preferably, cyclization of the methyl ester (66) is accomplished bytreatment with thionyl chloride, preferably an equimolar quantityrelative to the ester, using an aprotic solvent such as methylenechloride or tetrahydrofuran.

The oxazoline (67) is oxidized to compound (68) by refluxing with anoxidizing agent, preferably 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDO). Other oxidizing agents, such as activated manganese oxide or NiO₂are also useful. The reaction is preferably conducted in an aproticsolvent such as toluene, benzene or, preferably, dioxane and issubstantially complete in 1 to 24 hours.

The oxazole (68) can then be reduced with a reducing agent, such aslithium borohydride-methanol reducing system or, preferably, lithiumaluminum hydride in an aprotic polar solvent, such as tetrahydrofuran.The reaction is initiated at temperatures from −10° C. to ambienttemperature, preferably at about 0° C., and then stirred at ambienttemperature for from 30 minutes to 12 hours.

Halogenation of (69) is accomplished by treatment with a halogenatingagent such as triphenylphosphine and carbon tetrabromide, phosphorustribromide, phosphorus pentabromide, carbon tetrabromide or borontriphenylphosphine, preferably phosphorus tribromide, in an aproticpolar solvent such as methylenechloride or acetonitrile. The reaction ispreferably conducted at ambient temperatures for from 1-24 hours but mayalso be accomplished at temperatures of from −10° C. to ambienttemperatures.

In a displacement reaction under Finkelstein conditions, the halogen isreplaced with an appropriately substituted benzaldehyde.

Reductive amination of (70) as described in Scheme I(a), Step (e), aboveyields the desired product (71).

Compounds of formula I where Ar, X and Y and R⁴ are as defined as inScheme I(c-e), above, and m=0 can be prepared as demonstrated in SchemeXVI below.

Starting material (11) is coupled with oxazole starting material (70) inthe presence of a base, such as sodium hydride in an aprotic solvent,preferably tetrahydrofuran. The reaction is preferably conducted atambient temperatures for from 1 to 24 hours to prepare intermediateamide (72).

Reduction of intermediate (72) can be accomplished by treatment with areducing agent, such as borane-dimethylsulfide, to prepare (73).

Alternately, the coupling reaction can be accomplished by reacting (70)with (116) (prepared as described in Scheme I(a)(3)) followed byreduction of the carbonyl with a reducing agent, such as borane. Thereaction is conducted in an aprotic solvent, preferably tetrahydrofuran,at ambient temperatures.

Compounds where m is 2 can be prepared as described in Scheme XVII,below.

Starting material (59) is reacted with a halogenating agent such astriphenylphosphine and iodine, in the presence of a weak base. Thereaction can be conducted in an aprotic polar solvent at ambienttemperatures for from 1 to 24 hours.

In displacement reaction, the halogenated compound (60) is heated withsodium cyanide in an aprotic polar solvent such as dimethylsulfoxide forabout 1 to 2 hours to form the intermediate cyano compound (74).

The cyano compound (74) can then be reduced with a reducing agent, suchas diisobutylaluminum hydride, in a nonpolar solvent, such as toluene.Preferably, the reaction is initiated at −78° C. and then allowed towarm to ambient temperature for 1 to 2 hours.

The formyl compound (75) can then be reduced with a reducing agent, suchas sodium borohydride, in a solvent such diethylether to prepareintermediate (76).

Mitsunobu coupling of intermediate (76) with the appropriatelysubstituted hydroxy benzaldehyde gives (77) which can be isolated,purified and converted to the desired amine (78) by reductive amination.

Preparation of compounds where R¹ and R² are each independently—(C₁-C₆)alkoxy are prepared as described in Scheme XVIII, below.

Following the procedure described in Scheme I(a), Step (a), above,appropriately substituted benzoic acid (79) is converted to theintermediate benzamide (80).

Intermediate benzamide (80) may then by cyclized to form the ester (81)by heating at temperatures from 50° to 130° C. with 4-chloroacetoacetateunder an inert gas.

Reduction of the ester using, for example, lithium aluminum hydrideaffords the primary alcohol (82).

Following the procedure outlined in Scheme I(a), steps (d) and (e),amine (84) is prepared. Removal of the protecting group by, for example,hydrolysis achieves desired product (85).

Compounds where R3 and R4 taken together with the ring to which they areattached form a benzoxazole group are prepared as described in SchemeXIX, below.

An appropriately substituted benzoic acid (81) is coupled with2-hydroxy-5-methoxyaniline in the presence of an acid, such as boricacid, to form the intermediate benzoxazole (87).

Demethylation of (87) using, for example, borontribromide accomplishesthe alcohol (88). Preferably, the reaction is conducted in an organicsolvent such as methylene chloride at temperatures of about −10° to −70°C.

Preparation of (89) is achieved in an Ullman reaction by heating (88),preferably at temperatures of about 140° C., with an appropriatelysubstituted arylhalide, such as 4-bromobenzoldehyde in the presence ofpotassium carbonate and copper iodide.

Reductive amination, as described in Scheme I(a), step (e), affords(90).

Compounds where X is —O— and Y is —N— are accomplished as shown inScheme XX.

Oxadiazole (91) is prepared by, first, treating an appropriatelysubstituted benzoic acid (86) with thionyl chloride to prepare the acidchloride intermediate which may then be reacted with the appropriatelysubstituted alkylamidoxime, such as methylethylamidoxime.

Following steps (b)-(d) as described in Scheme XIX, above, desiredproduct (94) is achieved.

Compounds where X is —O— and

is a single bond can be prepared as described in Scheme XIX below.

Reduction of (95) is accomplished by treatment with a reducing agentsuch as lithium aluminum hydride. Preferably, the reaction is conductedin an aprotic polar solvent such as tetrahydrofuran at temperatures ofaround −10° C. to prepare the intermediate alcohol (96).

In a Mitsunobu coupling, as described in Scheme I(a), step (d), aldehyde(97) is prepared. Reductive amination, as described in Scheme I(a), step(e), affords (98).

Compounds where Ar is tetrehydronaphthyl are prepared as depicted inScheme XXII.

In a Mitsunobu coupling, as described in Scheme I, step (d), ester (99)is prepared. Hydrolysis of the ester is accomplished by treatment with abase, such as lithium hydroxide, to prepare the acid (100).

Cyclization to the tetrahydronaphthyl (101) is achieved by conversion ofthe acid first to the acid chloride, by treatment with, for examplethionyl chloride, then by reacting the acid chloride intermediate withethylene gas. Desired product (102) is accomplished by reductiveamination as described in Scheme I, step (e).

The intermediates and final products may be isolated and purified byconventional techniques, for example by concentration of the solvents,followed by washing of the residue with water, then purification byconventional techniques such as chromatography or recrystallization.

When Ar is phenyl substituted with one or two (C₁-C₆ alkyl)R⁶ groups,the present invention may have one or two stereo centers. The methods,formulations and compounds of the present invention encompass thediastereomers and the racemates and their individual stereo isomers.Diastereomeric pairs may be obtained according to procedures well knownin the art. For example, formation of a diastereomeric salt from aracemic amine can be accomplished by treatment with a chiral acid, suchas tartaric acid or diisopropylidene-keto-gulonic acid.

It will be readily appreciated by the skilled artisan that thesubstituted benzoic acid, amide, amine, alcohol, aldehyde, heterocyclic,imidazole and thiophenol starting materials are either commerciallyavailable or can be readily prepared by known techniques fromcommercially available starting materials. All other reactants used toprepare the compounds in the instant invention are commerciallyavailable.

The following examples further illustrate the preparation of thecompounds of this invention. The examples are illustrative only and arenot intended to limit the scope of the invention in any way.

EXAMPLE 12-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-ethylaminomethylphenoxy)ethyl)oxazolehydrochloride dihydrate

A. Preparation of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzamide

In a 22 L Morton flask, 749 g (3.0 mol) of3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, 533 g (3.3 mol)carbonyldiimidazole and tetrahydrofuran (THF) were combined and heatedslowly to reflux and allowed to reflux for 2.5 hours. The reactionmixture was cooled to 26° C. and concentrated aqueous ammonia was added.Stirring was continued for 2 hours and the reaction mixture was allowedto stand overnight. The contents were transferred to a flask and rinsedwith tetrahydrofuran (250 mL). The mixture was stirred, layers wereseparated, and the aqueous layer was saved. The organic layer was washedwith brine (2.5 L) followed by brine/deionized (DI) water (1 L/1.5 L).The organic layer was washed with 9.7 M hydrochloric acid(HCl)/deionized water (0.25 L/2.25 L), followed by 9.7 M hydrochloricacid/deionized water (0.5 L/2.8 L), and 9.7 M hydrochloricacid/deionized water/brine (0.5 L/1.5 L/1.5 L). The organic layer wasset aside while the combined aqueous layers were washed withtetrahydrofuran. The combined organic layers were washed with brine,dried with sodium sulfate (855 g) and filtered. The filtrate wasevaporated to 1011 g of a wet (water), white solid. Methylene chloridewas added and removed in vacuo. This procedure was repeated with ethylacetate (6 L, then 2 L) to produce a solid residue (779 g). The residuewas slurried in ethyl acetate and heptane, filtered, and dried in avacuum oven to yield the desired amide (736 g, 98.7%) as a white solid.

mp 257-260° C.

¹H M (DMSO-d₆, 300 MHz) δ7.75 (1H, s), 7.60 (2H, s), 7.30 (1H, s), 7.00(1H, s), 1.35 (18H, s).

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(carboxymethyl)oxazole

To 24.90 g (300 mmol) of the compound of step A, 55 mL (407 mmol) ofethyl 4-chloroacetoacetate was added. The mixture was heated to 130° C.under nitrogen for 2 hours. The reaction mixture was cooled to 90° C.and the volatiles were distilled from the reaction mixture under vacuumuntil the pot temperature reached 130° C. The thick residue was allowedto cool to 60° C. under vacuum. The vacuum was released and 100 mL ofmethanol was added to the mixture. The solution was cooled to 25° C. andthen 50% sodium hydroxide solution (50 mL) was added dropwise. Thereaction mixture temperature increased to 55° C. The mixture was stirred25 minutes, then concentrated aqueous hydrochloric acid (25 mL, 300mmol) was added dropwise to the reaction mixture to bring the pH to 7-8.The mixture was filtered and the cake was washed with methanol (2×50mL). The methanol was removed under vacuum, and then 1N hydrochloricacid (100 mL) and water (100 mL) were added. A gummy precipitate formed.The precipitate was dissolved by adding 500 mL of a 1:1 mixture oftert-butyl methyl ether (MTBE) and ethyl acetate. The resulting emulsionseparated into three layers overnight. The upper layer, containingdesired product by HPLC, was dried with sodium sulfate and concentratedin vacuo to give 30.8 g of a tan solid. This solid was dissolved in 2:1methanol:water (225 mL) at 75° C. The stirred mixture was allowed tocool to 25° C. over 1 hour, and stirred for another 2.5 hours. Themixture was filtered and the cake was washed with a total of 120 mL of2:1 methanol:water. Vacuum drying at 40° C. gave 21.94 g of thesubtitled product. A 19.9 g portion of the acid was recrystallized from300 mL of 1:1 heptane:toluene to give 17.77 g (62% overall yield) of thesubtitled product as a white solid.

mp 166-68° C.

¹H NMR (DMSO d-6, 300 MHz) δ12.49 (s, 1H, exchanges with D₂O), 7.93 (s,1H, ), 7.72 (s, 2H), 7.54 (s, 1H, exchanges with D₂O), 3.56 (s, 2H),1.41 (s, 18H).

Elemental analysis for C₁₉H₂₅NO₄: Calculated: C, 68.86; H, 7.60; N,4.23. Found: C, 68.86; H, 7.59; N, 4.32.

FDMS 331 (M⁺).

C. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole

In a 22 L flask, 757 g (2.28 mol) of the compound of step B wasdissolved in tetrahydrofuran. To the solution was added, very slowly atfirst and with water-bath cooling, 1 M borane tetrahydrofuran (4.8 L)After 1 hour the reaction mixture was quenched with methanol (650 mL)very slowly due to hydrogen evolution. The mixture was allowed to stirovernight. The solution was placed on a rotary evaporator and evaporatedto a foam (995 g). The residue was dissolved in tert-butyl methyl ether(11 L) and deionized water (4.9 L) and 50% sodium hydroxide (130 mL)were added and stirred then brine was added (3.6 L). Layers were allowedto separate yielding three layers. The lower two layers showed noproduct so they were discarded. The tert-butyl methyl ether layer waswashed with a mixture of 1 N sodium hydroxide (100 mL), deionized water(2 L), and brine (2 L). The organic layer was dried with sodium sulfate,filtered and evaporated to give 802 g of viscous residue. Toluene (1.4L) was added to the residue and the mixture was heated to 80° C. toobtain a solution. Heptane (6 L) was added, the solution was heated to93° C., and then cooled over 1.5 hours to 0-10° C. with an ice bath. Themixture was filtered and the cake was rinsed with 60:40 heptane/toluene(2 L). The solid was dried in a vacuum oven to yield 670 g of subtitledproduct. The solids Were recrystallized from toluene (2 L) and heptane(5.5 L) to yield 627 g (87% yield) of product as a white solid.

mp 119.5-21° C.

¹H NMR (CDCl₃, 300 MHz) δ1.48 (s, 18H), 2.8 (t, J=6.0 Hz, 2H), 3.97 (t,J=6.0 Hz, 2H), 5.52 (s, 1H), 7.42 (s, 1H), 7.82 (s, 2H).

D. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formylphenyloxy)ethyl)oxazole

The compound of step C (204.3 g, 644 mmol), triethylamine (100 mL, 716mmol) and methylene chloride (1.7 L) were stirred to give a solution.Methanesulfonyl chloride (81.3 g, 710 mmol) was added over 15 minutesand a water bath was used to keep the pot temperature below 31° C. Thereaction mixture was stirred and allowed to cool to 23° C. over 1.5hours. The reaction mixture was poured into a 4 L separatory funnel andthe flask was rinsed with methylene chloride (0.5 L). The organic layerwas washed with 1 N hydrochloric acid (3×1 L) and the combined aqueouslayers were back-extracted with methylene chloride (0.3 L). The combinedorganic layers and washed with a solution of brine (0.5 L) and deionizedwater (0.5 L). The organic layers were dried with sodium sulfate,filtered and evaporated to give 254 g of the mesylate as an oily foam.To the intermediate mesylate compound was added dimethyl sulfoxide(DMSO, 0.7 L) and a solution was obtained. In a separate flask,4-hydroxybenzaldehyde (89.6 g, 734 mmol), potassium t-butoxide (79.98 g,0.713 mmol) and dimethylsulfoxide (1.2 L) were combined and heated to45° C. to yield a brown solution. The mesylate compound indimethylsulfoxide was added all at once. The reaction mixture was heatedat 60-65° C. for 15 hours. An additional 0.5 L of dimethyl sulfoxide wasadded. The reaction temperature was increased to 70° C. and held therefor 2 hours. Then, 4-hydroxybenzaldehyde (3.92 g) and potassiumt-butoxide (3.59 g) were added to the reaction mixture. After 7 hours at70° C. the reaction mixture was allowed to cool to ambient temperature.Tert-butyl methyl ether (3.3 L) was added to the reaction mixture. Thesolution was extracted with 1N sodium hydroxide (4×2 L). The aqueouslayers were combined, back extracted with tert-butyl methyl ether (2×1L) and then discarded. The combined organic layers were washed withdeionized water (2 L), deionized water/brine (2 L), and brine (2 L). Theorganic layer was dried with sodium sulfate, filtered and evaporated togive a dark residue (267.3 g). The residue was dissolved in a mixture ofmethylene chloride (150 mL) and heptane (100 mL) and passed through achromatography unit with a silica gel (2.5 kg) column. The column waseluted with 1:1 heptane/methylene chloride (16 L), methylene chloride(12 L), and 6% ethyl acetate/methylene chloride. Fractions containingthe product as the major component were combined and evaporated to give196 g of an amber oil. The oil was dissolved in chloroform (200 mL), andtransferred to a flask with a mechanical stirrer. The flask was rinsedwith hexanes/chloroform (100 mL/25 mL) and hexanes (100 mL) and thewashes were added to the solution. After adding hexanes (1.8 L), thesolution was heated to reflux and 100 mL of distillate was collected.The mixture was cooled to 35° C. over 1.5 hours and then crystallizationoccurred. Using an ice/water bath, the solution was cooled to 6° C. over1.5 hours. The product was filtered, rinsed with 10% chloroform/hexanes(300 mL), and dried in a vacuum oven to obtain 153 g (56% yield) ofsubtitled product as a white solid.

mp 110-112° C.

HPLC assay showed 99.4% (by area) desired compound.

¹H NMR (CDCl₃, 300 MHz) δ1.45 (s, 18H), 3.10 (t, 2H, J=6 Hz), 4.38 (t,2H, J=6 Hz), 5.50 (s, 1H), 7.02 (d, J=7 Hz, 2H), 7.50 (s, 1H), 7.79 (d,J=7 Hz, 2H), 7.82 (s, 2H), 9.85 (s, 1H).

E. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-ethylaminomethylphenoxy)ethyl)oxazolehydrochloride hemihydrate

To 5.05 g (12 mmole) of the compound of step D dissolved in 50 ml. ofdry methanol under nitrogen was added 7.85 ml (120 mmole) ofmonoethylamine. The solution was stirred for 5 minutes then 6.8 ml (120mmole) of acetic acid was added and the mixture was stirred undernitrogen for 30 minutes. Sodium cyanoborohydride, 795 mg (12.6 mmole)was added and the reaction was stirred for 3 hours. An additional 500 mgof sodium cyanoborohydride was added and again stirred for an additionalhour. Ethyl acetate was then added and the mixture was washed withwater, saturated sodium bicarbonate and again with water. The organiclayer was dried, filtered then evaporated to give 5.44 g of crudeproduct which was chromatographed on 300 ml. silica, eluting withmethylene chloride/methanol/concentrated ammonia (90:10:1). Fractionscontaining the desired product were concentrated under vacuum thendissolved in diethyl ether. Hydrogen chloride gas was bubbled throughthe solution to provide an oil which was dissolved in acetone andstripped to dryness to give 3.4 g (54%) of title product as a whitefoam.

FDMS−M⁺450;

Elemental analysis for (C₂₈H₃₈N₂O₃.HCl.0.5H₂O) Calculated: C, 67.79; H,8.13; N, 5.65 Found: C, 67.97; H, 7.99; N, 5.74.

NMR (CDCl₃), δ1.40 (t, 3H, J=7 Hz), 1.49 (s, 18H), 2.92 (q, 2H, J=4 Hz),3.30 (t, 2H, J=7 Hz), 3.95 (t, 2H, J=7 Hz), 4.31 (t, 2H, J=7 Hz), 6.10(bs, 1H), 6.85 (d, 2H, J=9 Hz), 7.49 (d, 2H, J=9 Hz), 7.87 (s, 1H), 8.21(s, 2H), 9.59 (bs, 2H)

EXAMPLE 22-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-dimethylaminomethyl-phenoxy)ethyl)oxazolehydrochloride

Title compound was prepared from 1.26 g (3 mmole) of the compound ofexample 1D substantially in accordance with the procedure in Example 1Eabove using 200 mg (3.15 mmole) of sodium cyanoborohydride and 3.37 ml(30 mmole) of 40% aqueous dimethylamine. Such reaction provided 1.31 g(90%) of the title product as a white foam.

FDMS−M⁺450;

Elemental analysis for (C₂₈H₃₈N₂O₃.HCl) Calculated: C, 69.05; H, 8.07;N, 5.75 Found: C, 68.75; H, 7.94; H, 5.56.

NMR (CDCl₃), δ1.49 (s, 18H), 2.71 (d, 2H, J=3 Hz), 3.38 (t, 2H, J=7 Hz),4.10 (d, 2H, J=7 Hz), 4.44 (t, 2H, J=7 Hz), 6.08 (s, 1H), 6.95 (d, 2H,J=9 Hz), 7.50 (d, 2H, J=9 Hz), 7.74 (s, 1H), 8.23 (s, 2H).

EXAMPLE 32-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethylphenoxy)ethyl)oxazolehydrochloride hydrate

Title compound was prepared from 3.36 g (7.98 mmole) of the compound ofExample 1D substantially in accordance with the procedure in Example 1Eabove using 0.5 g (7.98 mmole) of sodium cyanoborohydride and 6.9 ml(79.8 mmole) of methylethylamine. The organic layer was chromatographedon silica gel using a methylene chloride/methanol gradient to give thefree base (2.79 g, 75%). The free base was dissolved in methylenechloride, treated with hydrogen chloride gas and evaporated to give 2.8g (93%) of the title product.

¹H NMR (CDCl₃), δ8.0 (s, 2H), 7.6 (s, 1H), 7.5 (d, J=9 Hz, 2H), 6.95 (d,J=9 Hz, 2H), 5.7 (s, 1H), 4.35 (t, J=7 Hz, 2H), 4.1 (m, 2H), 3.2 (m,3H), 2.9 (m, 1H), 2.6 (d, J=4 Hz, 3H), 1.5 (s, 18H), 1.45 (t, J=7 Hz,3H);

FDMS 464 (M⁺−HCl);

Elemental analysis for C₂₉H₄₁ClN₂O₃.H₂O Calculated: C, 67.10; H, 8.35;N, 5.40. Found: C, 66.99; H, 7.96; N, 5.29.

EXAMPLE 42-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-dimethylaminomethyl-phenoxy)ethyl)oxazolehydrochloride

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-formylphenoxy)ethyl)oxazole

To 4.44 g (14 mmole) of the compound of Example 1C dissolved intetrahydrofuran (THF) were added 1.94 g (16 mmole) of3-hydroxybenzaldehyde and 4.18 g (16 mmole) of triphenylphosphine (PPh₃)under nitrogen. The solution was chilled to −50° and a solution of 2.51ml (16 mmole) of diethyldiazodicarboxylate (DEAD) in 15 ml oftetrahydrofuran was added over 10 minutes with stirring. The bath wasremoved and the reaction stirred under nitrogen for 4 hours. Hydrogenperoxide (0.89 ml 30%) was added and the reaction was stirred for 15minutes, stripped, dissolved in 40 ml of methylene chloride and placedin the freezer. The diethoxycarbonylhydrazine was then filtered off andthe filtrate was chromatographed, eluting with a 5 to 20% acetone/hexanegradient over 30 minutes. The appropriate fractions were bulked andstripped to give 3.2 g (54%) of subtitled product.

NMR (CDCl₃), δ1.49 (s, 18H), 3.10 (t, 2H, J=7 Hz), 4.35 (t, 2H, J=7 Hz),5.50 (s, 1H), 7.20 (m, 1H), 7.44 (m, 3H), 7.51 (s, 1H), 7.84 (s, 2H),9.97 (s, 1H)

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-dimethylaminomethylphenoxy)ethyl)oxazolehydrochloride

Title compound was prepared from 3.2 g (7.6 mmole) of the compound ofstep A substantially in accordance with the procedure in Example 1Eusing 503 mg (8.0 mmole) of sodium cyanoborohydride and 9.5 ml (76mmole) of 40% dimethylamine. Such reaction provided 1.82 g white foam(49%) which was triturated with methylene chloride/isopropyl ether togive 1.25 g of title product.

FDMS−M⁺450;

Elemental Analysis for (C₂₈H₃₈N₂O₃.HCl) Calculated: C, 69.05; H, 8.07;N, 5.75 Found: C, 69.31; H, 8.13; N, 5.84.

NMR (CDCl₃), δ1.50 (s, 18H), 2.77 (d, 2H, J=5 Hz), 3.33 (t, 2H, J=7 Hz),4.15 (d, 2H, J=4 Hz), 4.48 (t, 2H, J=7 Hz), 5.95 (s, 1H), 6.98 (dd, 1H,J=2 Hz, 9 Hz), 7.12 (d, 1H, J=9 Hz), 7.32 (t, 1H, J=9 Hz), 7.53 (d, 1H,J=2 Hz), 7.88 (s, 1H), 8.16 (s, 2H).

EXAMPLE 52-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-n-propylaminomethyl-phenoxy)ethyl)oxazolehydrochloride

Title compound was prepared from 3.0 g (7.13 mmole) of the compound ofExample 1D substantially in accordance with the procedure in Example 1Eusing 471 mg of sodium cyanoborohydride and 5.82 ml (71.3 mole) ofmonopropylamine. Such reaction provided 1.67 g of the title product as awhite foam (47%).

FDMS−M⁺464;

Elemental analysis for (C₂₈H₃₈N₂O₃.HCl) Calculated: C, 69.51; H, 8.25;N, 5.59 Found: C, 69.80; H, 8.24; N, 5.46

NMR (CDCl₃), δ0.92 (t, 3H, J=7 Hz), 1.49 (s, 18H), 1.86 (m, 2H, J=7 Hz),2.71 (m, 2H, J=7 Hz), 3.28 (t, 2H, J=7 Hz), 3.94 (t, 2H, J=7 Hz), 4.30(t, 2H, J=7 Hz), 6.00 (s, 1H), 6.87 (d, 2H, J=9 Hz), 7.50 (d, 2H, J=9Hz), 7.74 (s, 1H), 8.17 (s, 2H), 9.70 (bs, 2H)

EXAMPLE 62-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-n-hexylaminomethyl-phenoxy)ethyl)oxazolehydrochloride

The title compound was prepared substantially as described in Example1E, except using N-hexylamine. The reaction was concentrated in vacuothen treated with 1:1 ethyl acetate:water (100 ml). Phases wereseparated, and the organics were washed with aqueous saturated sodiumbicarbonate (50 ml) followed by a brine wash (50 ml). Organics wereconcentrated in vacuo then treated with diethyl ether and silica gel (10g) and the resultant material was concentrated in vacuo to a flowablepowder. The powder was subjected to silica gel flash chromatographyeluting with methylene chloride (3×200 ml), methylene chloride:1%methanol (5×100 ml), 94:5:1 methylene chloride:methanol:ammoniumhydroxide (10×100 ml), 89:10:1 methylene chloride:methanol:ammoniumhydroxide (4×250 ml). Fractions containing desired product were combinedand concentrated in vacuo to afford 2.37 g of an oil. The oil wastreated with chloroform (75 ml) then hydrochloric acid gas. Theresultant solution was concentrated in vacuo to afford a foam which wastreated with hot methylene chloride (10 ml) then diisopropyl ether (10ml) and concentrated until turbidity was observed. The turbid solutionwas placed in freezer for approximately 2.5 hours. Insolubles werecollected by filtration, washed with diisopropyl ether and dried in avacuum oven at 40° C. overnight to afford 1.46 g of the title compound.

Mass Spectrum(FDMS): m/z 506 (M).

¹H NMR (CdCl₃): δ8.23 (s, 2H), 7.80 (s, 1H), 7.49 (d, J=8.3 Hz, 2H),6.87 (d, J=8.3 Hz, 2H), 6.07 (s, 1H), 4.32 (m, 2H), 3.93 (m, 2H), 3.32(m, 2H), 2.75 (m, 2H), 1.85 (m, 2H), 1.50 (m, 18H), 1.24 (m, 6H), 0.82(t, J=6.6 Hz, 3H).

Elemental analysis for C₃₂H₄₇ClN₂O₃: Calculated: C, 70.76; H, 8.72; N,5.16. Found: C, 70.68; H, 8.61; N, 5.16.

EXAMPLE 72-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-diethylaminomethyl-phenoxy)ethyl)oxazolehydrochloride dihydrate

Title compound was prepared from 4.21 g (10 mmole) of the compound ofExample 1D substantially in accordance with the procedure in Example 1Eusing 0.63 g (10 mmol) of sodium cyanoborohydride and diethylamine (10.3ml, 100 mmole). The reaction was allowed to continue for 21 hours. Theorganic layer was chromatographed on silica gel using a methylenechloride/methanol gradient to give the free base which was thendissolved in methlylene chloride, treated with hydrogen chloride gas andevaporated to provide 2.68 g (52%) of the title product.

¹H NMR (CDCl₃) δ8.05 (s, 2H), 7.6 (s, 1H), 7.55 (d, J=9 Hz, 2H), 6.95(d, J=9 Hz, 2H), 5.8 (s, 1H), 4.4 (t, J=7 Hz, 2H), 4.1 (d, J=5 Hz, 2H),3.25 (t, J=7 Hz, 2H), 3.0 (m, 4H), 1.5 (s, 18H), 1.4 (t, J=7 Hz, 6H);

FDMS 478 (M⁺−HCl);

Elemental analysis for C₃₀H₄₃ClN₂O₃.2H₂O: Calculated C, 64.32; H, 8.64;N, 5.00. Found: C, 63.94; H, 8.46; N, 4.80.

EXAMPLE 82-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-n-propyl-N-methylaminomethylphenoxy)ethyl)oxazolehydrochloride

The title compound was prepared substantially as described in Example1E, except using N-methyl-N-n-propylamine and chromatographing with 0 to10% (methanol:1% ammonium hydroxide):chloroform gradient over athirty-minute period. Fractions containing the desired product wereconcentrated in vacuo treated with chloroform (100 ml) and magnesiumsulfate, filtered and the filtrate was saturated with hydrogen chloridegas. The solution was concentrated in vacuo to a foam affording 3.40 g(68%) of the title compound.

Mass Spectrum(FDMS): m/z 478 (M).

¹H NMR (DMSOd₆): δ8.31 (s, 1H), 7.91 (s, 1H), 7.72 (s, 2H), 7.51 (s,1H), 7.16 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 4.22 (t, J=6.4 Hz,2H), 3.35 (s, 2H), 2.96 (t, J=6.4 Hz, 2H), 2.23 (t, J=7.3 Hz, 2H), 2.05(s, 3H), 1.41 (m, 20H), 0.83 (t, J=7.3 Hz, 3H).

Elemental analysis for C₃₀H₄₃ClN₂O₃.H₂O: Calculated: C, 67.58; H, 8.51;N, 5.25. Found: C, 67.65; H, 8.34; N, 5.33.

EXAMPLE 92-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-n-propyl-N-ethylaminomethylphenoxy)ethyl)oxazolehydrochloride

A solution of N-ethyl-N-propylamine (29.5 mmole, 2.58 g) in chloroform(10 ml) was saturated with hydrogen chloride gas. This solution wasconcentrated in vacuo then treated with ethanol (11 ml), triethylamine(29.5 mmole, 2.99 g), titanium IV isopropoxide (29.5 mmole, 8.40 g) and2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formylphenoxy)ethyl)oxazole(14.8 mmole, 6.22 g), prepared as described in Example 1D above. Thesuspension was stirred at room temperature for 4 hours then carefullytreated with sodium borohydride (22.2 mmole, 0.84 g) to avoid frothing.Reaction was stirred approximately 3 days before being treated with 2Nammonium hydroxide (23 ml). To this mixture was added methylene chloride(150 ml) and diatomaceous earth (20 g) and the mixture was filteredthrough a pad of diatomaceous earth and washed with methylene chloride(100 ml). The filtrate was washed with brine (1×50 ml) and the organiclayer was concentrated in vacuo to an oil, treated with chloroform andsubjected to preparatory chromatography. The material was eluted with 0to 10% (1% ammonium hydroxide:methanol):chloroform gradient over athirty-minute period. Fractions containing the desired product wereconcentrated in vacuo to an oil. The oil was treated with chloroform andsaturated with hydrogen chloride gas. This solution was concentrated invacuo to afford 4.78 g (61%) of the title compound.

mass Spectrum(FDMS): m/z 492 (M−HCl).

¹H NMR (DMSOd₆): δ10.45 (s, 1H), 7.94 (s, 1H), 7.73 (s, 2H), 7.53 (d,J=8.7 Hz, 2H), 7.03 (d, J=8.7 Hz, 2H), 4.28 (t J=6.5 Hz, 2H), 4.20 (t,J=5.2 Hz, 2H), 2.99 (m, 4H), 2.86 (m, 2H), 1.69 (m, 2H), 1.42 (s, 18H),1.24 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.3 Hz, 3H).

Elemental analysis for C₃₁H₄₅ClN₂O₃: Calculated: C, 70.36; H, 8.57; N,5.29. Found: C, 70.08; H, 8.32; N, 5.30.

EXAMPLE 102-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(2,4-bis(methylethylaminomethyl)phenoxy)ethyl)oxazoledihydrochloride

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(2,4-bis-formylphenoxy)ethyl)oxazole

In a flask, 4.75 g (15 mmole) of the compound of Example 1C, 2.36 g(15.75 mmole) of 3-formyl-4-hydroxybenzaldehyde, and 3.93 g (15 mmole)of triphenylphosphine were dissolved in 45 ml tetrahydrofuran withstirring, under nitrogen. The solution was chilled to −10° and asolution of 2.36 ml (15 mmole) diethyl azodicarboxylate in 15 ml.Tetrahydrofuran was added over 10 minutes, with stirring. The reactionexothermed to +1° C. The bath was removed and the reaction stirred undernitrogen for 18 hours. The reaction was then stripped, dissolved in aminimum amount of methylene chloride and placed in the freezer. Thediethoxycarbonylhydrazine was then filtered off and the filtrate waschromatographed, Prep 500, two columns, eluting with 0 to 20% ethylacetate/toluene gradient over 30 minutes. The appropriate fractions werebulked and stripped to give 3.3 g (49%) product which was used withoutfurther purification.

NMR (CDCl₃), δ1.48 (s, 18H), 3.17 (t, 2H, J=7 Hz), 4.53 (t, 2H, J=5 Hz),5.52 (s, 1H), 7.19 (d, 1H, 9 Hz), 7.53 (s, 1H), 7.84 (s, 2H), 8.11 (dd,1H, J=2 Hz,9 Hz), 8.32 (d, 1H, J=2 Hz), 9.94 (s, 1H), 10.48 (s, 1H)

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(2,4-bis(methylethylaminomethyl)phenoxy)ethyl)oxazoledihydrochloride hydrate

Title compound hydrochloride was prepared from 1.5 g (3.34 mmole) of theproduct of Step A substantially in accordance with the procedure inExample 9 using 4.0 ml (13.4 mmol) titanium IV isopropoxide and 1.15 ml(13.4 mmole) of methylethylamine and 0.38 g (10 mmole) sodiumborohydride. The organics were chromatographed on 100 ml silica, elutingwith methylene chloride/methanol and concentrated ammonia (90:10:1).Appropriate fractions were concentrated and dissolved in methylenechloride/isopropyl ether. Hydrogen chloride gas was bubbled in and theresultant residue was triturated with isopropyl ether to give 1.10 g(54%) of title product as a white foam.

FDMS−M⁺536;

Elemental analysis for (C₃₃H₄₉N₃O₃.2HCl.H₂O) Calculated: C, 63.45; H,8.52; N, 6.72 Found: C, 63.80; H, 8.53; N, 6.49.

NMR (CDCl₃), δ1.30-1.40 (m, 6H), 1.48 (s, 18H), 2.45-2.70 (m, 6H),2.79-3.35 (m, 6H), 3.90-4.30 (m, 4H), 4.38 (t, 2H, J=5 Hz), 5.58 (s,1H), 7.08 (d, 1H, J=9 Hz), 7.57 (s, 1H), 7.84 (s, 2H), 8.03 (d, 1H, J=9Hz), 8.13 (s, 1H)

EXAMPLE 112-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(2-hydroxyethyl)ethylaminomethylphenoxy)ethyl)oxazolehydrochloride

To a stirred solution of N-ethylethanolamine (1.95 ml, 20 mmole) inethanol (25 ml) was added titanium IV isopropoxide (5.9 ml, 20 mmole),then the compound of Example 1D (4.21 g, 10 mmole). The reaction wasstirred for 4 hours, then sodium borohydride (0.57 g, 15 mmole) wasadded. After 20 hours at room temperature, the reaction was poured into75 ml 2N ammonium hydroxide and diluted with methylene chloride. Themixture was filtered though diatomaceous earth and the filtrate wasextracted with brine. The organic layer was dried over sodium sulfate,evaporated to dryness, and chromatographed on silica gel using amethylene chloride/methanol gradient to give the free base (3.56 g,72%). The free base was dissolved in methylene chloride (86 ml), treatedwith hydrogen chloride gas, and evaporated to give desired product (3.92g, 100%):

¹H NMR (CDCl₃) δ8.0 (s, 2H), 7.6 (s, 1H), 7.5 (d, J=9 Hz, 2H), 6.95 (d,J=9 Hz, 2H), 5.7 (s, 1H), 4.35 (t, J=7 Hz, 2H), 4.2 (m, 2H), 3.9 (m,2H), 3.2 (t, J=7 Hz, 2H), 3.15 (m, 4H), 1.5 (m, 21H);

FD MS 494 (M⁺−HCl);

Elemental Analysis for C₃₀H₄₃ClN₂O₄.0.5H₂O: Calculated: C, 66.71; H,8.21; N, 5.19. Found: C, 66.47; H, 8.10; N, 5.20.

EXAMPLE 122-(3,5-di-t-butyl-4-methoxyphenyl)-4-(2-(4-N-bis[hydroxyethyl]aminomethylphenoxy)ethyl)oxazolehydrochloride

The title compound was prepared substantially as described in Example 11except using diethanolamine. The material was subjected to preparatorychromatography, eluting with a gradient of 0 to 10% (1% ammoniumhydroxide/methanol):chloroform over a thirty minute period. Fractionscontaining the title compound were combined and concentrated in vacuo toafford an oil. The oil was treated with chloroform then hydrogenchloride gas and concentrated in vacuo to afford 817 mg of the titlecompound as a foam.

Mass Spectrum (FDMS): m/z 510. (M−HCl).

1H NMR (CDCl₃): δ7.96 (s, 2H), 7.58 (s, 1H), 7.48 (d, J=8.6 Hz, 2H),6.97 (d,J=8.6, 2H), 5.68 (s, 1H), 4.35 (m, 4H), 4.01 (m, 4H), 3.33 (m,4H), 3.17 (m,2H), 1.48 (s, 18H).

Elemental analysis for C₃₀H₄₃ClN₂O₅+0.3 mole H₂O: Calculated: C, 65.21;H, 7.95; N,5.07. Found: C, 65.18; H, 7.95; N, 4.67.

EXAMPLE 132-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-[N-methyl-N-(3-piperidin-3-yl)propyl)aminomethyl]phenoxy)ethyl)oxazoledihydrochloride

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-aminomethylphenoxy)ethyl)oxazole

The subtitled compound was prepared substantially as described inExample 11, except using the methylamine hydrochloride salt. The crudematerial was subjected to preparatory chromatography. The material waseluted with 0 to 10% (1% ammonium hydroxide:methanol):chloroformgradient over a thirty minute period. Fractions containing desiredproduct were reduced in vacuo, dried over sodium sulfate, filtered andconcentrated in vacuo, to afford 6.74 g (62%) of the title compound.

Mass Spectrum(FDMS): m/z 436 (M).

¹H NMR (CdCl₃): δ7.83 (s, 2H), 7.46 (s, 1H), 7.42 (d, J=8.3 Hz, 2H),6.92 (d, J=8.3 Hz, 2H), 5.30 (bs, 1H), 4.22 (t J=6.5 Hz, 2H), 3.93 (s,2H), 3.03 (t, J=6.5 Hz, 2H), 2.46 (s, 3H), 1.48 (s, 18H).

Elemental analysis for C₂₇H₃₆N₂O₃: Calculated: C, 74.28; H, 8.31; N,6.42. Found: C, 74.39; H, 8.51; N, 6.47.

B. Preparation of2-{(3,5-di-t-butyl-4-hydroxyphenyl)-4-[N-methyl-N-(3-(N′-tert-butoxycarbonylpiperid-3-yl)propyl)aminomethyl]phenoxy)ethyl}oxazole

A red solution of the compound of step A, (9.2 mmole, 4.01 g), indimethylformamide (dimethylformamide, 18 ml) was treated with 60%(wt/wt) sodium hydride (20.2 mmole, 808 mg). The suspension was stirredfor 30 minutes at 24° C. then treated with a solution ofN-tert-butoxycarbonyl-3-(3-bromopropyl)piperidine (8.4 mmole, 2.56 g) indimethylformamide (5 ml). Next, the suspension was heated at 80° C. for4 hours then cooled to 24° C. The reaction treated with 10% aqueoussodium bisulfate (25 ml), water (10 ml) and 3/2 ethyl acetate:hexane (50ml). The phases were separated and the aqueous phase was extracted with3:2 ethyl acetate:hexane (2×50 ml). Combined organics were washed withbrine (2×50 ml), dried over sodium sulfate, filtered and concentrated invacuo to afford 6.67 g of an oil. The crude material was subjected topreparatory chromatography. The material was eluted with 0 to 10% (1%ammonium hydroxide:methanol):chloroform gradient over a thirty-minuteperiod. Fractions containing the desired product were reduced in vacuo,dried over sodium sulfate, filtered and concentrated in vacuo, to afford4.19 g of the title compound. This material contained some impuritiesand was taken on to the next step without further purification.

Mass Spectrum(FDMS): m/z 662 (M+1).

¹NMR (CdCl₃): δ7.83 (s, 2H), 7.50 (s, 1H), 7.19 (d, J=8.4 Hz, 2H), 6.88(d, J=8.4 Hz, 2H), 5.49 (s, 1H), 4.27 (t J=6.6 Hz, 2H), 3.91 (m, 1H),3.40 (s, 2H), 3.07 (t, J=6.6 Hz, 2H), 2.72 (m, 1H), 2.32 (t, J=7.3 Hz,2H), 2.15 (s, 3H), 1.80 (m, 1H), 1.37-1.69 (m, 26H), 1.22 (m, 2H).

C. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-[N-methyl-N-(3-(N′-tert-butoxycarbonyl-piperid-3-yl)propyl)aminomethyl]phenoxy)ethyl)oxazolehydrochloride

A solution of the compound of Step B (3.15 mmole, 2.09 g) in diethylether (20 ml) was treated with hydrogen chloride gas for approximately10 minutes. The resulting heavy suspension was stirred an additional 20minutes, filtered and washed with diethyl ether (20 ml) to afford 2.01 g(91%) of the subtitled compound.

Mass Spectrum(FDMS): m/z 661 (M).

¹H NMR (CdCl₃): δ8.13 (s, 2H), 7.66 (s, 1H), 7.50 (d, J=8.5 Hz, 2H),6.96 (d, J=8.5 Hz, 2H), 5.91 (s, 1H), 4.41 (t J=5.9 Hz, 2H), 4.10 (m,2H), 3.84 (s, 2H), 3.30 (t, J=5.8 Hz, 2H), 2.96 (m, 1H), 2.78 (m, 2H),2.63 (m, 3H), 2.49 (dd, J=9.9, 12.9 Hz, 1H), 1.85 (m, 2H), 1.50 (s,27H).

Elemental analysis for C₄₀H₆₀ClN₃O₅: Calculated: C, 68.89; H, 8.53; N,6.03. Found: C, 68.65; H, 8.45; N, 6.02.

D. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-[N-methyl-N-(3-(piperidin-3-yl)propyl)aminomethyl]phenoxy)ethyl)oxazoledihydrochloride

To a solution of the compound of Step C (3.0 mmole, 2.01 g) inchloroform (20 ml) was added thiophenol (6.07 mmole, 0.67 g). Next,hydrogen chloride gas was passed through this solution for approximately30 minutes then stirred overnight at 24° C. before being concentrated invacuo to a foam. The material was taken up into hot methylene chloride(10 ml) then tetrahydrofuran (15 ml) was added while heating thesolution. The solution was boiled down to approximately 12 ml totalvolume, cooled to approximately −22° C. before tetrahydrofuran (10 ml)was added, resulting in the formation of a precipitate. The suspensionwas filtered, the insolubles were transferred with methylene chlorideand the volume was reduced to approximately 5 ml. Tetrahydrofuran (20ml) was added and the solution was boiled down to approximately 5 ml.Next, diethyl ether (20 ml) was added to the hot solution resulting inthe formation of a gum. The suspension was cooled to 24° C. the gum wastriturated and insolubles were collected by filtration and washed withdiethyl ether (20 ml). Insolubles were resuspended with stirring in hotdiethyl ether (150 ml). After heating for approximately 30 minutes(keeping volume between 100-150 ml) the insolubles were collected byfiltration and washed with hot diethyl ether (100 ml). Insolubles weredried in a vacuum oven at 60° C. overnight to afford 1.32 g (72%) of thetitle compound.

Mass Spectrum(FDMS): m/z 562 (M+1).

¹H NMR (CdCl₃): δ8.00 (s, 2H), 7.62 (s, 1H), 7.50 (d, J=8.1 Hz, 2H),6.95 (d, J=8.1 Hz, 2H), 5.74 (s, 1H), 4.35 (m, 2H), 4.26 (m, 2H), 3.59(m, 1H), 3.37 (m, 1H), 3.20 (m, 2H), 3.04 (m, 1H), 2.66-2.89 (m, 4H),2.55 (m, 1H), 1.80-2.25 (m, 7H), 1.49 (s, 18H), 1.11-1.41 (m, 3H).

Elemental analysis for C₃₅H₅₃Cl₂N₃O₃: Calculated C, 66.23; H, 8.42; N,6.62. Found: C, 66.47; H, 8.67; N, 6.39.

EXAMPLE 142-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminoethylphenoxy)ethyl)oxazolehydrochloride heptahydrate

A. Preparation of N-formyl-N-ethyl-p-hydroxyphenethylamine

To a suspension of 1,1′-carbonyldiimidazole (326 mmole, 52.81 g) intetrahydrofuran (164 ml) cooled to 0° C., was added dropwise 96% formicacid (326 mmole, 14.99 g) over a 26 minute period. Reaction stirred at0° C. for 30 minutes then a light suspension ofN-ethyl-p-hydroxyphenethylamine (102 mmole, 16.88 g) in tetrahydrofuran(66 ml) was added over a 10 minute period. Reaction then stirred at 22°C. for 170 minutes before being treated with methanol (10 ml). Afterstirring for 90 minutes, reaction was concentrated in vacuo to an oilcontaining crystals. The mixture was taken up into methylene chlorideand subjected to preparatory chromatography eluting with a gradient of 0to 5% methanol:methylene chloride over a thirty-minute period. Thefractions containing the title compound were combined, concentrated invacuo to afford 13.46 g of an oil that slowly crystallizes out.Fractions containing title compound and impurities were resubjected topreparatory column chromatography under the same conditions describedabove to afford an additional 2.61 g of the title compound.

mp (° C.):85

Mass Spectrum (FDMS): m/z 193. (M).

¹H NMR (DMSOd₆): δ9.20 (s, 1H), 8.01 (s, ½H), 7.72 (s, 1/2H), 7.00 (d,J=8.4 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 3.34 (dt,J=7.2 Hz, 2H), 3.21 (dq, J=7.1 Hz, 2H), 2.64 (dt, J=7.2 Hz, 2H), 1.04(dt, J=7.1 Hz, 2H).

Elemental analysis for C₁₁H₁₅NO₂ Calculated: C, 68.37; H, 7.82; N, 7.25.Found: C, 68.56; H, 7.81; N, 7.49.

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-formyl-N-ethylaminoethylphenoxy)ethyl)oxazole

The title compound was prepared substantially as described in Example 4above except using N-formyl-N-ethyl-p-hydroxyphenethylamine and 0.7M(mmole alcohol/ml tetrahydrofuran) reaction solution. After stirring at24° C. for approximately 22 hours, the reaction was concentrated invacuo. The filtrate was concentrated in vacuo to an oil, treated withethyl acetate and subjected to preparatory chromatography. The materialwas eluted with 45% ethyl acetate. Fractions containing desired productwere concentrated in vacuo then resubjected to preparatorychromatography. The material was eluted with 0 to 20% ethyl acetate/(93%chloroform:hexane) gradient over a thirty minute period. Fractionscontaining the desired product were concentrated in vacuo thenresubjected to preparatory chromatography. The material was eluted with5 to 30% acetone/hexane gradient over a thirty minute period. Fractionscontaining desired product were concentrated in vacuo to afford 3.01 g(19%) of the subtitled compound as a foam.

Mass Spectrum(FDMS): m/z 493 (M+1).

¹H NMR (DMSOd₆): δ8.01 (s, 1/2H), 7.91 (s, 1/2H), 7.74 (s, 1H), 7.72 (s,2H), 7.52 (bs, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 4.20(t, J=6.5 Hz, 2H), 3.40 (dt, J=7.1 Hz, 2H), 3.22 (dq, J=7.1 Hz, 2H),2.96 (t, J=6.5 Hz, 2H), 2.71 (dt, J=7.1 Hz, 2H), 1.41 (s, 18H), 1.04(dt, J=7.1 Hz, 3H).

Elemental analysis for C₃₀H₄₀N₂O₄: Calculated: C, 73.14; H, 8.18; N,5.69. Found: C, 73.30; H, 8.44; N, 5.90.

C. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminoethylphenoxy)ethyl)oxazole

Sulfuric acid (6.0 mmole, 0.597 g) was carefully added dropwise over aneight minute period to a cooled suspension of lithium aluminum hydride(12.2 mmole, 0.462 g) in tetrahydrofuran (THF, 18 ml). After theaddition was complete, the ice bath was removed. Approximately one hourafter the addition, the reaction was cooled to 0° C., then a solution ofthe compound of Step B in tetrahydrofuran (4 ml) was added over a tenminute period. The reaction was stirred at 24° C. for 3 hours thenquenched with water (12.2 mmole, 214 μL). Next, chloroform (200 ml) wasadded followed by 5N hydrochloric acid (50 ml). Phases were separatedand the aqueous phase was extracted with chloroform (2×50 ml). Combinedorganic phases were washed with brine (1×50 ml) then dried over sodiumchloride, filtered and concentrated in vacuo to afford 5.8 g of an oilthat contained some solids. The material was treated with ethyl acetate(250 ml) then washed with saturated aqueous sodium bicarbonate (2×50ml). The organics were dried over sodium sulfate, filtered thenconcentrated in vacuo to afford 2.77 g of an oil. The material wastreated with chloroform and subjected to preparatory chromatography. Thematerial was eluted with 0 to 10% (1% ammoniumhydroxide:methanol):chloroform gradient over a 30 minute period.Fractions containing the desired product were concentrated in vacuo toan oil. This material was taken up into chloroform then saturated withhydrogen chloride gas. The solution was concentrated in vacuo to afford1.35 g (43%) of the title compound as a foam.

Mass Spectrum(FDMS): m/z 478 (M+1).

¹H NMR (DMSOd₆): δ7.92 (s, 1H), 7.72 (s, 2H), 7.54 (s, 1H), 7.21 (d,J=8.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H), 4.22 (t, J=6.6 Hz, 2H), 3.19 (m,4H), 2.98 (m, 4H), 2.76 (d, J=4.9 Hz, 3H), 1.41 (s, 18H), 1.22 (t, J=7.2Hz, 3H).

Elemental analysis for C₃₀H₄₀N₂O₄.0.7H₂O Calculated: C, 68.28; H, 8.48;N, 5.31. Found: C, 68.20; H, 8.41; N, 5.35.

EXAMPLE 152-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-ethyl-N-methylaminobutyl)phenoxyethyl)oxazolehydrochloride

A. Preparation of 4-(4-hydroxyphenyl)butyl bromide

A solution of triphenylphosphine (144.1 mmole, 37.80 g) in methylenechloride (556 ml) was treated with bromine (144.1 mmole, 23.03 g) untila pale yellow color persisted. After stirring approximately 15 minutes,a solution of 4-(4-hydroxyphenyl)butanol (96.1 mmole, 15.97 g) andimidazole (192.2 mmole, 13.08 g) in methylene chloride (355 ml) wasadded over a 15 minute period. Approximately 4 hours later, the reactionsuspension was filtered and the filtrate was reduced in volume. To thereduced filtrate was added silica gel and the suspension was reduced todryness. This material was filtered and the first six fractions wereeluted with 10% ethyl acetate:hexane. Fractions 7 through 12 were elutedwith 20% ethyl acetate:hexane. Fractions 7 through 10 were combined,reduced in volume, dried over sodium sulfate, filtered and concentratedin vacuo to afford 19.32 g (88%) of the title compound as an oil.

Mass Spectrum (FDMS): m/z 230. (M+1).

1H NMR (CDCl₃): δ7.03 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.4 Hz, 2H), 4.59(s, 2H),3.40 (t, J=6.7 Hz, 2H), 2.56 (m, 2H), 1.83-1.90 (m, 2H),1.70-1.77 (m, 2H).

Elemental analysis for C₁₀H₁₃BrO: Calculated: C,52.42; H, 5.72. Found:C, 52.24; H, 5.61.

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(4-bromobutyl)phenoxyethyl)oxazole

The title compound was prepared substantially as described in Example 4except using the compound of Step A. The reaction was concentrated invacuo to an oil. The oil was treated with chloroform (25 ml),triturated, then treated with diatomaceous earth and filtered through apad of diatomaceous earth. The filtrate was reduced in volume thensubjected to preparatory chromatography. The material was eluted with agradient of 20 to 35% diethyl:ether:hexane over a 30 minute period.Fractions 4-15 were combined, concentrated in vacuo thenrechromatographed eluting with a gradient of 20 to 35% diethylether:hexane over a 30 minute period. Fractions 8-16 were combined,concentrated in vacuo then rechromatographed eluting with a gradient of5 to 20% ethyl acetate:(33% chloroform:67% hexane) over a 30 minuteperiod. Fractions 7-9 were combined, dried over sodium sulfate, filteredand concentrated in vacuo to afford 10.51 g (49%) of the title compound.

Mass Spectrum (FDMS): m/z 529. (M+1).

1H NMR (CDCl₃): δ7.83 (s, 2H), 7.50 (s, 1H), 7.08 (d, J=8.5 Hz, 2H),6.85 (d, J=8.5 Hz, 2H), 5.49 (s, 1H), 4.25 (t, J=6.6 Hz, 2H), 3.41 (t,J=6.6 Hz, 2H), 3.06 (t, J=6.6 Hz, 2H), 2.58 (t, J=7.4 Hz, 2H), 1.88 (m,2H), 1.72 (m, 2H), 1.49 (s,18H).

Elemental analysis for C₂₉H₃₈BrNO₃: Calculated: C, 65.90; H, 7.25; N,2.65. Found: C, 66.14; H, 7.26; N, 2.36.

C. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-ethyl-N-methylaminobutyl)phenoxyethyl)oxazolehydrochloride

A solution of N-methylethyl amine (7.8 mmole, 0.46 g) indimethylformamide (21 ml) was treated with sodium hydride (7.8 mmole,0.68 g). The suspension was heated at 35° C. for 15 minutes. Next, thesuspension was treated with a solution of a compound of Step B (8.5mmole, 4.51 g) in dimethylformamide (21 ml). The suspension was thenheated at 70° C. for approximately 4.5 hours before additionalN-methylethyl amine (15.6 mmole, 0.92 g) was added. Forty five minuteslater the reaction was cooled to 22° C., treated with ethyl acetate (50ml), hexane (25 ml) and 10% aqueous sodium sulfate 950 ml). The phaseswere separated and the aqueous phase was extracted with 2:1 ethylacetate:hexane (3×75 ml). Combined organics were washed with brine(2×100 ml), dried over sodium sulfate, filtered and concentrated invacuo to afford 4.16 g of an oil. The oil was treated with chloroform,filtered through a pad of diatomaceous silica end washed withchloroform. The filtrate was subjected to preparatory silica gelchromatography. The material was eluted with a gradient of 0 to 10% (1%ammonium hydroxide:methanol):chloroform over a thirty minute period.Fractions containing the desired product were combined, concentrated invacuo, taken up into chloroform (100 ml), washed with 1:1 saturatedaqueous sodium bicarbonate:water (50 ml) then brine (50 ml). Theorganics were dried over sodium sulfate, filtered and concentrated invacuo to afford 1.6 g of an oil. The oil was treated with chloroform (50ml) then saturated with hydrogen chloride gas. This solution wasconcentrated in vacuo to a foam. The foam was treated withtetrahydrofuran (THF) and boiled on a steam bath while slowly addingdiisopropyl ether. The tetrahydrofuran was boiled off, resulting in theproduct oiling out. The remaining solvent was decanted off and isopropylether (10 ml) was added. The biphasic solution was boiled on steam bath,solvent was decanted and the remaining material was pulled on housevacuum overnight to afford 1.38 g of the title compound as a foam.

Mass Spectrum (FDMS): m/z 506. (M).

1H NMR (CDCl₃): δ7.86 (s, 2H), 7.52 (s, 1H), 7.06 (d, J=8.5 Hz, 2H),6.85 (d,J=8.5 Hz, 2H), 5.54 (s, 1H), 4.26 (t, J=6.5 Hz, 2H), 3.08 (t,J=6.5 Hz, 2H), 2.88(m, 3H), 2.67 (d, J=4.9 Hz, 3H), 2.60 (t, J=7.3 Hz,2H), 1.66-1.85 (m, 3H),1.38-1.48 (m, 24H).

Elemental analysis for C₃₂H₄₇ClN₂O₃: Calculated: C, 70.76; H, 8.72; N,5.16. Found: C, 70.52; H, 8.56; N, 5.41.

EXAMPLE 162-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-N-ethyl-N-methylaminopropyl)phenoxy)ethyl)oxazolehydrochloride

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(2-cyanoethyl)phenoxyethyl)oxazole

The title compound was prepared substantially as described in Example 4except using 3-(4-hydroxyphenyl)propionitrile. The reaction wasconcentrated in vacuo to an oil. The oil was treated with chloroform (75ml), triturated, and filtered. The filtrate was washed with saturatedaqueous sodium bicarbonate (2×250 ml) and 10% sodium bisulfate (1×250ml). The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo to afford a dark oil. The oil was treated withmethylene chloride and subjected to preparatory silica gelchromatography. Material was eluted with a gradient of 10 to 25% ethylacetate:hexane over a thirty minute period. Fractions containing thetitle compound were combined and concentrated in vacuo to afford 29.57 gof an oil. This material was resubjected to preparatory silica gelchromatography eluting with a gradient of 15 to 35% diethyl ether:hexaneover a thirty minute period. Fractions containing the title compoundwere combined and concentrated in vacuo to afford 20.57 g of foam. Thismaterial was resubjected to preparatory silica gel chromatographyeluting with a gradient of 10 to 30% acetone:hexane over a thirty minuteperiod. Fractions containing the title compound were combined andconcentrated in vacuo to afford 14.71 g of foam. This material containedtrace impurities and was taken on to the next step without furtherpurification.

Mass Spectrum (FDMS): m/z 446. (M).

1H NMR (DMSOd₆): δ7.92 (s, 1H), 7.73 (s, 2H), 7.52 (s, 1H), 7.19 (d,J=8.6 Hz,2H), 6.91 (d, J=8.6 Hz, 2H), 4.23 (t, 2H), 2.96 (t, 2H), 2.78(m, 4H), 1.42 (s,18H).

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(2-formylethyl)phenoxyethyl)oxazole

To a cooled solution of the compound of Step A (32.9 mmole, 14.68 g) intoluene (105 ml) at −78° C., was added a 1.0 molar solution ofdiisobutylaluminum hydride (42.7 mmole, 42.7 ml) over a seventeen minuteperiod. The reaction was then stirred at 22° C. for 1 hour and quenchedwith methanol (4.1 ml). The suspension was cooled to 0° C. and treatedwith a saturated solution of ammonium hydroxide (300 ml). After stirringfor 1.5 hours, the reaction was treated with 50% sulfuric acid until abiphasic solution resulted. The mixture was then treated with ethylacetate (250 ml) and the phases were separated. The aqueous phase wasextracted with ethyl acetate (3×100 ml). The combined organic phaseswere washed with brine (2×200 ml), dried over sodium sulfate, filteredand concentrated in vacuo to an oil. The oil was subjected topreparatory silica gel chromatography. Material was eluted with agradient of 0 to 10% methanol:toluene over a thirty minute period.Fractions containing subtitled compound were combined, concentrated invacuo to afford 11.76 g of an oil. This material was taken on to thenext step without further purification.

Mass Spectrum (FDMS): m/z 449. (M).

1H NMR (DMSOd₆): δ9.70 (s, 1H), 7.91 (s, 1H), 7.73 (s, 2H), 7.53 (s,3H), 7.12(d, J=8.6Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 4.20 (t, J=6.5 Hz,2H), 2.96 (t,J=6.5 Hz, 2H), 2.75 (m, 4H), 1.42 (s, 18H).

C. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-N-ethyl-N-methylaminopropyl)phenoxy)ethyl)oxazolehydrochloride

The title compound was prepared substantially as described in Example 11except using the compound of step B and N-methylethylamine. The materialwas subjected to preparatory chromatography eluting with a gradient of 0to 5% (1% ammonium hydroxide:methanol):chloroform over a thirty minuteperiod. Remaining fractions eluted with 5% (1% ammoniumhydroxide:methanol):chloroform. Fractions containing desired productwere combined, concentrated in vacuo, taken up into chloroform (100 ml)and washed with saturated sodium bicarbonate (10 ml) and water (15 ml)followed by water (25 ml). The organic layer was dried over sodiumsulfate and filtered. The filtrate was saturated with hydrogen chloridegas and concentrated in vacuo to afford 1.61 g of the title compound asa foam.

Mass Spectrum (FDMS): m/z 492. (M−HCl).

1H NMR (CDCl₃): δ7.84 (s, 2H), 7.51 (s, 1H), 7.07 (d, J=8.6 Hz, 2H),6.86 (d,J=8.6 Hz, 2H), 5.51 (s, 1H), 4.25 (t, J=6.6 Hz, 2H), 2.84-3.09(m, 6H), 2.67 (m,5H), 2.13-2.21 (m, 2H), 1.48 (s, 18H), 1.39 (t, J=7.3Hz, 3H).

Elemental analysis for C₃₁H₄₅ClN₂O₃+0.2 mole H₂O: Calculated: C, 69.89;H, 8.58; N,5.26. Found: C, 69.88; H, 8.73; N, 5.32.

EXAMPLE 172-(3,5-di-t-butyl-4-methoxyphenyl)-4-(2-(4-N-ethyl-N-methylaminomethylphenoxy)ethyl)oxazolehydrochloride

A. Preparation of2-(3,5-di-t-butyl-4-methoxyphenyl)-4-(2-(4-formylphenoxy)ethyl)oxazole

A solution of the compound of Example 1D (8.4 mmole, 3.54 g) and methyliodide (67.3 mmole, 9.54 g) in tetrahydrofuran (40 ml) anddimethylformamide (4 ml) was treated with sodium hydride (60% wt/wt,16.8 mmole, 0.67 g). After stirring 31 hours at 22° C., the reaction wastreated with water (10 ml) and the pH was adjusted from 12.6 to 5.4 with1N hydrochloric acid. The biphasic solution was reduced in volume toremove tetrahydrofuran then ethyl acetate was added (100 ml) followed by10% aqueous sodium bisulfate (50 ml). The phases were separated and theorganic phase was dried over sodium sulfate and filtered. The filtratewas subjected to preparatory silica gel chromatography, eluting with agradient of 20 to 45% ethyl acetate:hexane over a thirty minute period.Fractions containing subtitled compound were combined and concentratedin vacuo to afford 3.57 g of an oil. Material was taken on to next stepwithout further purification.

Mass Spectrum (FDMS): m/z 435. (M).

1H NMR (CDCl₃): δ9.88 (s, 1H), 7.90 (s, 2H), 7.82 (d, J=8.8 Hz, 2H),7.53 (s,1H), 7.02 (d, J=8.8 Hz, 2H), 4.36 (t, J=6.5 Hz, 2H), 3.70 (s,3H), 3.11 (t, J=6.5 Hz, 2H), 1.46 (s, 18H).

B. Preparation of2-(3,5-di-t-butyl-4-methoxyphenyl)-4-(2-(4-N-ethyl-N-methylaminomethylphenoxy)ethyl)oxazolehydrochloride

The title compound was prepared substantially as described in Example 11except using the compound of Step A. The material was subjected topreparatory chromatography eluting with a gradient of 0 to 10% (1%ammonium hydroxide:methanol):chloroform over a thirty minute period.Fractions containing title compound were combined and concentrated invacuo to a foam. The foam was treated with chloroform then saturatedwith hydrogen chloride gas. This solution was concentrated in vacuo toafford 2.2 g of the title compound as a foam.

Mass Spectrum (FDMS): m/z 478. (M−HCl).

1H NMR (DMSOD6): δ10.46 (s, 1H), 8.00 (s, 1H), 7.83 (s, 2H), 7.51 (d,J=8.6 Hz, 2H), 7.04 (dd, J=8.6, 2H), 4.09-4.31 (m, 4H), 3.68 (s, 3H),2.92-3.11 (m, 4H),2.57 (d, J=4.8 Hz, 3H), 1.42 (s, 18H), 1.25 (t, J=7.2Hz, 3H).

Elemental analysis for C₃₀H₄₃ClN₂O₃+0.2 mole H₂O: Calculated: C, 69.46;H, 8.43; N, 5.40. Found: C, 69.23; H, 8.47; N, 5.53.

EXAMPLE 182-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(4-dimethylaminobutyryl)phenyloxy)ethyl)oxazolehydrochloride

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(4-chlorobutyryl)phenyloxy)ethyl)oxazole

To a stirred solution of the compound of Example 1C (5.68 g, 17.92mmole) in tetrahydrofuran (54 ml) was added4-chloro-4′-hydroxybutyrophenone (3.56 g, 17.92 mmole) andtriphenylphosphine (5.16 g, 19.71 mmole). After cooling to −20° C., asolution of diethylazodicarboxylate (3.1 ml, 19.71 mmole) intetrahydrofuran (18 ml) was added dropwise over 15 min. The reaction wasallowed to warm to room temperature and stir for 5 hours, at which timeit was diluted with diethyl ether and extracted with water and brine.The organic layer was dried over sodium sulfate, evaporated to dryness,and chromatographed on silica gel using a hexane-acetone gradient togive the intermediate chloroketone (4.77 g, 53%):

¹H NMR (CDCl₃) δ7.95 (d, J=9 Hz, 2H), 7.85 (s, 2H), 7.5 (s, 1H), 6.95(d, J=9 Hz, 2H), 5.5 (s, 1H), 4.35 (t, J=7 Hz, 2H), 3.7 (t, J=6 Hz, 2H),3.1 (m, 4H), 2.2 (m, 2H), 1.5 (s, 18H);

FD MS 497 (M⁺).

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(4-dimethylaminobutyryl)phenyloxy)ethyl)oxazolehydrochloride

To a stirred solution of the chloroketone (5.09 g, 10.2 mmole) inacetone (51 ml) was added sodium iodide (7.66 g, 51 mmole). The reactionwas heated at 50° C. for 28 hours, evaporated to dryness, andredissolved in methylene chloride and water. The organic layer wasextracted with brine, dried over sodium sulfate, and evaporated todryness to give the intermediate iodoketone, which was used withoutfurther purification. The iodoketone was dissolved in toluene (30 ml),cooled to 0° C., and treated with anhydrous dimethylamine (0.79 ml, 12mmole). The reaction was heated to 80° C. for 3 hours, then allowed tocool to room temperature. A white precipitate was filtered, and thefiltrate was diluted with ethyl acetate and saturated sodiumbicarbonate. The organic layer was extracted with 0.1N sodiumthiosulfate and brine, dried over sodium sulfate, evaporated to dryness,and chromatographed on silica gel using a methylene chloride/methanolgradient to give the free base (1.82 g, 35%). The free base wasdissolved in methylene chloride (50 ml ) treated with hydrogen chloridegas, and evaporated to give desired product (1.87 g, 96%):

¹H NMR (CDCl₃) δ8.0 (s, 2H), 7.95 (d, J=9 Hz, 2H), 7.6 (s, 1H), 6.95 (d,J=9 Hz, 2H), 5.8 (s, 1H), 4.4 (t, J=7 Hz, 2H), 3.3-3.1 (m, 6H), 2.8 (d,J=4 Hz, 6H), 2.25 (m, 2H), 1.5 (s, 18H);

FDMS 506 (M⁺−HCl);

Elemental analysis for C₃₁H₄₃ClN₂O₄: Calculated: C, 68.55; H, 7.98; N,5.16. Found: C, 68.36; H, 7.90; N, 5.34.

EXAMPLE 192-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(1-dimethylaminoethyl)phenyloxy)ethyl)oxazolehydrochloride monohydrate

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-acetylphenyloxy)ethyl)oxazole

To a stirred solution of 10 g (31.5 mmole) of the compound of Example 1Cabove, in tetrahydrofuran (95 ml) was added 4-hydroxyacetophenone (4.29g, 31.5 mmole) and triphenylphosphine (9.09 g, 34.7 mmole). Aftercooling to −20° C., a solution of diethylazodicarboxylate (5.5 ml, 34.7mmole) in tetrahydrofuran (31 ml) was added dropwise over 15 min. Thereaction was allowed to warm to room temperature and stir for 2.5 hours,at which time it was diluted with diethyl ether and extracted with waterand brine. The organic layer was dried over sodium sulfate, evaporatedto dryness, and chromatographed on silica gel using a toluene-ethylacetate gradient to give the subtitled compound (8.5 g, 62%):

¹H NMR (CDCl₃) δ7.95 (d, J=9 Hz, 2H), 7.85 (s, 2H), 7.5 (s, 1H), 6.95(d, J=9 Hz, 2H), 5.5 (s, 1H), 4.35 (t, J=7 Hz, 2H), 3.1 (t, J=7 Hz, 2H),2.55 (s, 3H), 1.5 (s, 18H);

FDMS 435 (M⁺).

E. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(1-dimethylaminoethyl)phenyloxy)ethyl)oxazolehydrochloride

Title compound was prepared substantially in accordance with theprocedure in Example 1E above using the compound of Step A, 1.23 g (19.5mmole) of sodium cyanoborohydride and dimethylamine (19.4 ml, 293mmole), heating to 60° C. for 24 hours. The organic layer waschromatographed on silica gel using a methylene chloride/methanolgradient to give the free base which was dissolved in methylenechloride, treated with hydrogen chloride gas, and evaporated to give8.31 g (80%) of the title product.

¹H NMR (CDCl₃) δ11.6 (bs, 1H), 8.05 (s, 2H), 7.6 (s, 1H), 7.45 (d, J=9Hz, 2H), 6.95 (d, J=9 Hz, 2H), 5.8 (s, 1H), 4.4 (t, J=7 Hz, 2H), 4.15(m, 1H), 3.25 (t, J=7 Hz, 2H), 2.7 (d, J=4 Hz, 3H), 2.55 (d, J=4 Hz,3H), 1.85 (d, J=7 Hz, 3H), 1.5 (s, 18H);

FDMS 464 (M⁺−HCl);

Elemental analysis for C₂₉H₄₁ClN₂O₃.H₂O: Calculated: C, 67.10; H, 8.35;N, 5.40. Found: C, 67.00; H, 8.04; N, 5.24.

EXAMPLE 202-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethyl-3-methylphenoxy)ethyl)oxazolehydrochloride hydrate

A. Preparation of 3-methyl-allyloxybenzene

m-Cresol 10.4 ml (100 mmole), 10.8 ml (125 mmole) allyl bromide, and16.56 g (120 mmole) of potassium carbonate were stirred in 50 ml ofacetone and refluxed, with stirring, under nitrogen, for 18 hours. Thereaction was cooled, the insoluble inorganics were filtered off and thefiltrate was stripped to give 14.0 g (95%) of subtitled product, whichwas used without further purification.

NMR (CDCl₃), δ2.33 (s, 3H), 4.51-4.54 (m, 2H), 5.26-5.45 (m, 2H),6.00-6.13 (m, 1H), 6.72-6.78 (m, 2H), 7.17 (t, 1H, J=9 Hz).

E. Preparation of 4-allyloxy-2-methylbenzaldehyde

N-methyl formanilide 19.4 ml (158 mmole), was chilled to 13° C., whereit began to solidify. Phosphorus oxychloride, 13.7 ml (147 mmole), wasadded with stirring, under nitrogen. After 25 minutes, the temperaturewas 45° C. and the reaction had again begun to solidify. The compound ofStep A, 14 g (95 mmole), was added and the mixture was stirred andheated in a 70° C. oil bath. The reaction exothermed to 95° C. Stirringwas continued under nitrogen for 30 minutes. The bath was removed andwhen the temperature reached 35°, the mixture was dissolved inchloroform. Ice was added and the layers were separated and washed oncewith water, twice with saturated sodium bicarbonate, once again withwater and once with brine. The organic layer was chromatographed on 450ml silica, eluting with chloroform to give 13.54 g (81%) of subtitledproduct which was used without further purification.

NMR (CDCl₃), δ2.64 (s, 3H), 4.61 (m, 2H), 5.30-5.49 (m, 2H), 6.00-6.12(m, 1H), 6.74-6.87 (m, 2H), 7.73 (m, 1H), 10.11 (s, 1H).

C. Preparation of 2-methyl-4-hydroxybenzaldehyde

The compound of Step B, 13.54 g (76.9 mmole), 1.72 g (7.69 mmole)palladium acetate, and 12.09 g (46.2 mmole) triphenylphosphine weremixed in a 250 ml flask. Formic acid, 3.2 ml (84.6 mmole), was added andthe reaction was swirled. Within 15 seconds, the reaction foamed,exothermed and formed a gum which was dissolved in ethyl acetate, washedonce with sodium bicarbonate and once with brine. The organic layer waschromatographed on 350 ml silica, eluting with 20%, then 40% ethylacetate/hexane. The fractions were combined and the product crystallizedfrom methylene chloride/hexane to give 3.61 g (35%) of product which wasused without further purification.

NMR (CDCl₃), δ2.50 (s, 3H), 6.70 (d, 1H, J=2 Hz), 6.78 (dd, 1H, J=2 Hz,9 Hz), 7.75 (d, 1H, J=9 Hz), 10.36 (s, 1H)

D. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formyl-3-methylphenyloxy)ethyl)oxazole

Subtitled compound was prepared from 8.0 g (25.2 mmole) of the compoundof Example 1C substantially in accordance with the procedure in Example4A using 3.61 g (26.5 mmole) of the compound of Step C, 6.62 g (25.2mmole) triphenylphosphine and 3.97 ml (25.2 mmol)diethylazodicarboxylate. The crude product was chromatographed on silicaeluting with methylene chloride. The appropriate fractions were bulkedand stripped to give 5.05 g (46%) of subtitled product which was usedwithout further purification.

NMR (CDCl₃), δ1.48 (s, 18H), 2.64 (s, 3H, J=5 Hz), 3.11 (t, 2H, J=5 Hz),4.35 (t, 2H, J=5 Hz), 5.54 (s, 1H), 6.77 (d, 1H, J=2 Hz), 6.86 (dd, 1H,J=2 Hz, 9 Hz), 7.51 (s, 1H), 7.74 (d, 1H, J=9 Hz), 7.86 (s, 1H), 10.11(s, 1H)

E. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethyl-3-methylphenoxy)ethyl)oxazolehydrochloride hydrate

Title compound was prepared from 4.54 g (10.4 mmole) of the compound ofStep D substantially in accordance with the procedure of Example 1Eabove using 8.9 ml (104 mmole) of methylethylamine, 5.59 ml (104 mmole)of acetic acid and 693 mg (11 mmole) of sodium cyanoborohydride. Suchreaction provided 1.89 g. (35%) of title product as a white foam.

FDMS−M⁺ 478;

Elemental analysis for (C₃₀H₄₂N₂O₃.HCl.0.75H₂O: Calculated: C, 68.02; H,8.48; N, 5.35 Found: C, 68.16; H, 8.48; N, 5.30.

NMR (CDCl₃), δ1.41 (t, 3H, J=7 Hz), 1.48 (s, 18H), 2.41 (s, 3H), 2.65(d, 2H, J=5 Hz), 2.96 (m, 1H), 3.24 (m, 2H), 4.07-4.27 (m, 3H), 5.84 (s,1H), 6.80 (m, 2H), 7.63 (m, 2H), 8.07 (s, 2H)

EXAMPLE 212-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-chloro-4-N-methyl-N-ethylaminomethylphenoxy)ethyl)oxazolehydrochloride hemihydrate

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-chloro-4-formylphenoxy)ethyl)oxazole

Subtitled compound was prepared from 6.34 g (20 mmole) of the compoundof Example 1C substantially in accordance with the procedure in Example4A using 3.60 g (23 mmole) of 2-chloro-4-hydroxybenzaldehyde, 6.03 g (23mmole) of triphenylphosphine and 3.62 ml (23 mmole)diethylazodicarboxylate. The crude product was chromatographed, elutingwith methylene chloride. The appropriate fractions were bulked andstripped to give 5.64 g (62%) of subtitled product which was usedwithout further purification.

NMR (CDCl₃), δ1.48 (s, 18H), 3.09 (t, 2H, J=7 Hz), 4.35 (t, 2H, J=7 Hz),5.52 (s, 1H), 6.90, (dd, 1H, J=2 Hz, 9 Hz), 6.97 (d, 1H, J=2 Hz), 7.49(s, 1H), 7.84 (s, 2H), 7.87 (d, 1H, J=9 Hz), 10.32 (s, 1H)

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-chloro-4-N-methyl-N-ethylaminomethylphenoxy)ethyl)oxazolehydrochloride hemihydrate

Title compound was prepared from 4.58 g (10 mmole) of the compound ofStep A substantially in accordance with the procedure in Example 1Eabove using 6.54 ml (100 mmole) of methylethylamine, 5.75 ml (300 mmole)acetic acid and 661 mg (10.5 mmole) of sodium cyanoborohydride. Suchreaction provided 1.24 g. (23%) of title product as a white foam.

FDMS−M⁺ 498;

Elemental analysis for (C₂₉H₃₉N₂O₃Cl.HCl.0.5H₂O: Calculated: C, 63.96;H, 7.59; N, 5.14 Found: C, 63.83; H, 7.83; N, 5.10

NMR (CDCl₃), δ1.47 (s, 21H), 2.65 (d, 3H, J=5 Hz), 2.99 (m, 1H), 3.13(t, 2H, J=7 Hz), 3.23 (m, 1H), 4.20-4.40 (m, 4H), 5.62 (s, 1H), 6.94 (d,1H, J=9 Hz), 6.98 (s, 1H), 7.53 (s, 1H), 7.91 (s, 2H), 8.05 (d, 1H, J=9Hz)

EXAMPLE 222-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-hydroxy-4-N-methyl-N-ethylaminomethylphenoxy)ethyl)oxazolehydrochloride hemihydrate

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-hydroxy-4-formylphenoxy)ethyl)oxazole

Subtitled compound was prepared from 12.68 g (40 mmole) of the compoundof Example 1C substantially in accordance with the procedure in Example4A above using 6.35 g (46 mmole) of 2,4-dihydroxybenzaldehyde, 12.05 g(46 mmole) of triphenylphosphine and 7.24 ml (46 mmole)diethylazodicarboxylate. The crude product was chromatographed onsilica, eluting with methylene chloride. The appropriate fractions werecombined and stripped of solvent to give 9.2 g (53%) of subtitledproduct which was used without further purification.

NMR (CDCl₃), δ1.49 (s, 18H), 3.09 (t, 2H, J=5 Hz), 4.33 (t, 2H, J=5 Hz),5.51 (s, 1H), 6.47 (d, 1H, J=2 Hz), 6.55 (dd, 1H, J=2 Hz, 9 Hz), 7.42(d, 1H, J=9 Hz), 7.50 (s, 1H), 7.84 (s, 2H), 9.71 (s, 1H), 11.47 (s, 1H)

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(3-hydroxy-4-N-methyl-N-ethylaminomethylphenoxy)ethyl)oxazolehydrochloride hemihydrate

Title compound was prepared from 3.18 g (7.28 mmole) of the compound ofStep A substantially in accordance with the procedure in Example 1Eabove using 4.76 ml (72.8 mmole) methylethylamine, 4.16 ml (72.8 mmole)acetic acid and 481 mg (7.64 mmole) of sodium cyanoborohydride and thereaction was allowed to proceed for 2 days. Such reaction provided 1.23g. (33%) of the title product as a white foam.

FDMS−M⁺ 480;

Elemental analysis for (C₂₉H₄₀N₂O₄.HCl.0.5H₂O) Calculated: C, 66.21; H,8.05; N, 5.32 Found: C, 66.01; H, 8.49; N, 5.09

NMR (CDCl₃), δ1.41 (t, 3H, J=7 Hz), 1.48 (s, 18H), 2.65 (d, 2H, J=5 Hz),2.96 (m, 1H), 3.24 (m, 2H), 4.07-4.27 (m, 3H), 6.01 (s, 1H), 6.36 (d,1H, J=9 Hz), 6.94 (d, 1H, J=2H), 7.26 (m, 1H), 7.84 (s, 1H), 8.13 (s,2H), 10.75 (bs, 1H)

EXAMPLE 232-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethyl-3,5-dimethylphenyloxy)ethyloxazolehydrochloride hydrate

A. Preparation of 3,5-dimethyl-allyloxy benzene

3,5-Dimethylphenol, 12.2 g (100 mmole), 10.8 ml (125 mmole) of allylbromide, and 16.56 g (120 mmole) of potassium carbonate was dissolvedand then refluxed in 50 ml acetone, with stirring, under nitrogen for 18hours. The reaction was cooled, the insoluble inorganics were filteredoff and stripped to give 16.2 g (100%) of subtitled product, which wasused without further purification.

NMR (CDCl₃), δ2.29 (s, 6H), 4.50 (m, 2H), 5.25-5.44 (M, 2H), 5.99-6.12(m, 2H), 6.56 (s, 2H), 6.60 (s, 1H)

B. Preparation of 4-allyloxy-2,6-dimethyl-benzaldehyde

N-methyl formanilide, 20.5 ml (166 mmole), was chilled to 13°, where itbegan to solidify. Phosphorus oxychloride, 14.4 ml (155 mmole), wasadded with stirring, under nitrogen. After 25 minutes, the temperaturewas 45°. 3,5-Dimethylallyloxy benzene, 16.2 g (100 mmole), prepared asdescribe above, was added with stirring and heated in a 70° C. oil bath.The reaction exothermed to 93° C. and was stirred under nitrogen for 30minutes. The bath was removed and when the temperature reached 35°, theproduct was dissolved in chloroform. Ice was added, the layers wereseparated and washed once with water, twice with sodium bicarbonate,once with water and once with brine. The product was chromatographeddown 500 ml of silica, eluting with chloroform to give 9.67 g (51%) ofsubtitled product which was used without further purification.

NMR (CDCl₃), δ2.60 (s, 6H), 4.59 (m, 2H), 5.29-5.45 (m, 2H), 6.01-6.11(m, 1H), 6.60 (s, 2H), 10.47 (s, 1H)

C. Preparation of 2,6-dimethyl-4-hydroxy-benzaldehyde

4-Allyloxy-2,6-dimethyl-benzaldehyde, 9.67 g (50.9 mmole), 1.14 g (5.09mmole) of palladium II acetate, and 8.00 g (30.5 mmole) oftriphenylphosphine was mixed in a flask. Formic acid, 2.11 ml (56mmole), was added and the mixture was swirled in a 80° oil bath. Within15 seconds the reaction exothermed and turned very dark. The gum wasdissolved in ethyl acetate, washed once in sodium bicarbonate, once inwater, and once in brine then chromatographed on 350 ml silica, using20%, then 40% ethyl acetate/hexane. Fractions were bulked andcrystallize from methylene chloride/hexane to give 3.90 g (51%) ofsubtitled product which was used without further purification.

NMR (CDCl₃), δ2.64 (s, 6H), 6.74 (s, 2H), 7.26 (bs, 1H), 10.09 (s, 1H)

D. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formyl-3,5-dimethylphenyloxy)ethyl)oxazole

Title compound was prepared from 7.85 g (24.8 mmole) of the compound ofExample 1C substantially in accordance with the procedure in Example 4Aabove using 3.9 g (26 mmole) 2,6-dimethyl-4-hydroxybenzaldehyde, 6.49 g(24.8 mmole) triphenylphosphine and 3.90 ml (24.8 mmole)diethylazodicarboxylate. The reaction was stirred under nitrogen for 18hours. Hydrogen peroxide, 1.38 ml 30%, was added and the reaction wasstirred for an additional 30 minutes, stripped, dissolved in 40 mlmethylene chloride and placed in the freezer. Thediethoxycarbonylhydrazine was then filtered off and the filtrate waschromatographed, eluting with methylene chloride. The appropriatefractions were bulked and stripped to give 6.73 g (60%) of subtitledproduct which was used without further purification.

NMR (CDCl₃), δ1.48(s, 18H), 2.59 (s, 6H), 3.12 (t, 2H, J=9 Hz), 4.34 (t,2H, J=9 Hz), 5.58 (s, 1H), 6.61 (s, 2H), 7.52 (s, 1H), 7.89 (s, 2H),10.47 (s, 1H)

E. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-methylaminomethyl-3,5-dimethylphenyloxy)ethyl)oxazolehydrochloride monohydrate

Title compound was prepared substantially in accordance with theprocedure in Example 1E above using 5.02 g (11.2 mmole) of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formyl-3,5-dimethylphenyloxy)ethyl)oxazole,9.59 ml (112 mmole) methylethyl amine, 6.40 ml (112 mmole) acetic acid,and 741 mg (11.76 mmole) sodium cyanoborohydride. Ethyl acetate wasadded and the mixture was washed once with water, once with saturatedsodium bicarbonate, twice with water and once with brine. The mixturewas dried, stripped of organics and chromatographed, eluting withmethylene chloride/methanol 92:8. Fractions were bulked, stripped oforganics and dissolved in methylene chloride/isopropyl ether. Hydrogenchloride gas was bubbled through the solution and the mixture wasconcentrated and triturated with isopropyl ether to give 4.47 g (69%)white foam.

FDMS−M+ 492;

Elemental Analysis for C₃₁H₄₄N₂O₃.HCl.H₂O Calculated: C, 68.05; H, 8.66;N; 5.12 Found: C, 68.06; H, 8.84; N, 4.77

NMR (CDCl₃), δ1.49 (s, 18H), 1.55 (t, 3H, 5 Hz), 2.48 (s, 6H), 3.23 (m,2H), 3.36 (m,t, 2H, J=5 Hz), 3.98 (m, 1H), 4.30-4.40 (m, 3H), 6.05 (s,1H), 6.66 (s, 2H), 7.73 (s, 1H), 8.22 (s, 2H), 11.20 (bs, 1H)

EXAMPLE 242-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethyl-2-chlorophenyloxy)ethyl)oxazolehydrochloride

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formyl-2-chlorophenyloxy)ethyl)oxazole

Subtitled compound was prepared from 3.17 g (10 mmole) of compound ofExample 1C, 1.72 g (11 mmole) 3-chloro-4-hydroxybenzaldehyde, 2.62 g (10mmole) triphenylphosphine and 1.57 ml (10 mmole) diethylazodicarboxylatesubstantially in accordance with the procedure in Example 4A above. Thereaction was chromatographed, eluting with 4% methanol/methylenechloride. The appropriate fractions were bulked and stripped to give3.51 g (77%) product which was used without further purification.

NMR (CDCl₃), δ1.48 (s, 18H), 3.17 (t, 2H, J=7 Hz), 4.42 (t, 2H, J=7 Hz),5.51 (s, 1H), 7.08 (d, 1H, J=9 Hz), 7.61 (s, 1H), 7.75 (dd, 1H, J=2 Hz,9 Hz), 7.84 (s, 2H), 7.90 (d, 1H, J=2 Hz), 9.84 (s, 1H)

E. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethyl-2-chlorophenyloxy)ethyl)oxazolehydrochloride

Title compound was prepared from 1.75 g of the compound of Step Asubstantially in accordance with the procedure in Example 9, using 0.66ml (7.7 mmole) methylethylamine, 2.28 ml (7.7 mmole) titanium IVisopropoxide and 220 mg (5.74 mole) sodium borohydride except that thereduction was stirred for 18 hours. Ammonia (6.3 ml, 2N) was added togive a thick suspension. Methylene chloride and diatomaceous earth wereadded and the suspension was filtered through diatomaceous earth. Thefiltrate was washed once with brine, dried and the organics stripped andchromatographed, eluting with methylene chloride/methanol/concentratedammonia 90:5:0.5. The fractions were bulked, stripped of solvent anddissolved in methylene chloride/isopropyl ether. Hydrogen chloride gaswas bubbled in and the material was concentrated and triturated withisopropyl ether to give 1.21 g (59%) white foam.

FDMS−M⁺ 498;

Elemental analysis for C₂₉H₃₉N₂O₃Cl.HCl Calculated: C, 65.04; H, 7.53;N, 5.23 Found: C, 65.30; H, 7.72; N, 5.22

NMR (CDCl₃), δ1.48 (m, 21H), 2.63 (d, 3H, J=5 Hz), 2.88-2.92 (m, 1H),3.15 (m, 3H, J=5 Hz), 3.97-4.16 (m, 2H), 4.34 (t, 2H, J=5 Hz), 5.53 (s,1H), 7.03 (d, 1H, J=9 Hz), 7.48 (d, 1H, J=2 Hz), 7.60 (s, 1H), 7.65 (dd,1H, J=2 Hz, 9 Hz), 7.85 (s, 1H)

EXAMPLE 252-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethyl-1-naphthyloxy)ethyl)oxazolehydrochloride hemihydrate

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formyl-(2naphthyloxy)ethyl)oxazole

Subtitled compound was prepared from 7.925 g (25 mmole) of the compoundof Example 1C substantially in accordance with the procedure in Example4A using 4.95 g (28.75 mmole) of 4-hydroxy-1-naphthaldehyde, 7.53 g(28.75 mmole) of triphenylphosphine and 4.52 ml (28.75 mmole)diethylazodicarboxylate. The crude product was chromatographed withmethylene chloride. The appropriate fractions were bulked and strippedto give 4.08 g (35%) product which was used without furtherpurification.

NMR (CDCl₃), δ1.48 (s, 18H), 3.26 (t, 2H, J=6 Hz), 4.57 (t, 2H, J=6 Hz),5.51 (s, 1H), 6.97 (d, 1H, J=9 Hz), 7.56 (m, 2H), 7.69 (t, 1H, J=9 Hz),7.85 (s, 1H), 7.91 (d, 1H, J=9 Hz), 8.33 (d, 1H, J=9 Hz), 9.30 (d, 1H,J=9 Hz), 10.20 (S, 1H)

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethyl-1-naphthyloxy)ethyl)oxazolehydrochloride hemihydrate

Title compound was prepared from 3.41 g (7.24 mmole) of the compound ofStep A substantially in accordance with the procedure in Example 1Eabove using 4.74 ml (72.4 mmole) of methylethylamine, 4.14 ml (12.4mmol) acetic acid and 480 mg (7.6 mmole) of sodium cyanoborohydride. Thecrude product was chromatographed eluting with a gradient of methylenechloride/methanol/1% concentrated ammonia 100:0:00 to 90:10:1 over 10minutes. Crude product was dissolved in methylene chloride/isopropylether, treated with hydrogen chloride gas and the resulting oiltriturated with isopropyl ether to give 1.84 g (46%) white foam.

FDMS−M⁺ 514;

Elemental analysis for C₃₃H₄₂N₂O₃.HCl.0.5H₂O Calculated: C, 70.76; H,7.92; N, 5.00 Found: C, 70.52; H, 8.22; N, 4.72

NMR (CDCl₃), δ1.13 (t, 3H, J=6 Hz), 1.49 (s, 18H), 2.65 (d, 2H, J=5 Hz),2.96 (m, 1H), 3.24 (m, 1H), 3.58 (m, 2H), 4.07-4.27 (m, 2H), 6.01 (s,1H), 6.97 (d, 1H, J=9 Hz), 7.56 (t, 1H, J=9H), 7.69 (t, 1H, J=9 Hz),7.82 (m, 2H), 8.14 (d, 1H, J=9 Hz), 8.24 (m, 3H)

EXAMPLE 262-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(morpholin-4-yl-methyl)phenyloxy)ethyl)oxazolehydrochloride

Title compound was prepared from the compound of Example 1D (4.21 g, 10mmole) substantially in accordance with the procedure in Example 1Eusing morpholine (8.72 ml, 100 mmole) and sodium cyanoborohydride (0.63g, 10 mmole). The methanol was evaporated and the residue was dissolvedin ethyl acetate and saturated sodium bicarbonate. The organic layer wasextracted with brine, dried with sodium sulfate, evaporated to dryness,and chromatographed on silica gel using a hexane-isopropanol gradient togive the free base (3.68 g, 75%). The free base was dissolved inmethylene chloride, treated with hydrogen chloride gas, and evaporatedto give desired product (3.68 g, 93%).

¹H NMR (CDCl₃) δ10.95 (bs, 1H), 7.9 (s, 2H), 7.6 (s, 1H), 7.5 (d, J=9Hz, 2H), 6.95 (d, J=9 Hz, 2H), 5.5 (s, 1H), 4.25 (m, 4H), 4.1 (d, J=5Hz, 2H), 3.9 (dd, J=10, 3 Hz, 2H), 3.25 (d, J=10 Hz, 2H), 3.05 (t, J=7Hz, 2H), 2.9 (m, 2H), 1.5 (s, 18H);

FDMS 492 (M⁺−HCl);

Elemental analysis for C₃₀H₄₁ClN₂O₄; Calculated: C, 68.10; H, 7.81; N,5.29. Found: C, 67.93; H, 7.73; N, 5.17.

EXAMPLE 272-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(4-methylpiperazin-1-yl-methyl)phenyloxy)ethyl)oxazole dihydrochloride

Title compound was prepared from 5.05 g (12 mmole) of the compound ofExample 1D substantially in accordance with the procedure in Example 1Eabove using N-methylpiperazine (13.3 ml, 120 mmole) and sodiumcyanoborohydride (0.75 g, 12 mmole). The methanol was evaporated and theresidue was dissolved in ethyl acetate and saturated sodium bicarbonate.The organic layer was extracted with brine, dried with sodium sulfate,evaporated to dryness, and chromatographed on silica gel using amethylene chloride/methanol gradient to give the free base (4.53 g,75%). The free base was dissolved in methylene chloride, treated withhydrogen chloride gas, and evaporated to give desired product (4.53 g,87%).

¹H NMR (CDCl₃) δ7.95 (s, 2H), 7.55 (d, J=9 Hz, 2H), 7.5 (s, 1H), 6.95(d, J=9 Hz, 2H), 5.5 (s, 1H), 4.3 (t, J=7 Hz, 2H), 4.15 (s, 2H), 3.9 (m,2H), 3.75 (m, 2H), 3.45 (m, 4H), 3.05 (t, J=7 Hz, 2H), 2.9 (s, 3H), 1.5(s, 18H);

FDMS 505 (M⁺−HCl);

Elemental analysis for C₃₁H₄₅Cl₂N₃O₃: Calculated: C, 64.35; H, 7.84; N,7.26. Found: C, 64.07; H, 7.67; N, 7.32.

EXAMPLE 282-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(4-acetylpiperazin-1-yl-methyl)phenyloxy)ethyl)oxazolehydrochloride

Title compound was prepared from the compound of Example 1D (4.21 g, 10mmole) substantially in accordance with the procedure in Example 1Eusing N-acetylpiperazine (12.82 g, 100 mmole) and sodiumcyanoborohydride (0.63 g, 10 mmole). The methanol was evaporated and theresidue was dissolved in ethyl acetate and saturated sodium bicarbonate.The organic layer was extracted with brine, dried with sodium sulfate,evaporated to dryness, and chromatographed on silica gel using amethylene chloride/methanol gradient to give the free base (3.96 g,74%). The free base was dissolved in methylene chloride, treated withhydrogen chloride gas, and evaporated to give desired product (3.94 g,93%).

¹H NMR (CDCl₃) δ10.8 (bs, 1H), 7.95 (s, 2H), 7.55 (d, J=9 Hz, 2H), 7.5(s, 1H), 6.95 (d, J=9 Hz, 2H), 5.6 (s, 1H), 4.7 (d, J=13 Hz, 1H), 4.35(t, J=7 Hz, 2H), 4.15 (m, 2H), 3.85 (d, J=13 Hz, 1H), 3.45 (m, 4H), 3.15(t, J=7 Hz, 2H), 2.65 (m, 2H), 2.1 (s, 3H), 1.5 (s, 18H);

FDMS 533 (M⁺−HCl);

Elemental analysis for C₃₂H₄₄ClN₃O₄.1.2H₂O: Calculated: C, 64.95; H,7.90; N, 7.10. Found: C, 64.67; H, 7.51; N, 6.97.

EXAMPLE 292-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-thiomorpholinylmethylphenoxy)ethyl)oxazole

Title product was prepared from the compound of example 1D substantiallyin accordance with the procedure in Example 11, except usingthiomorpholine, and conducting the reaction at room temperature. Thematerial was eluted with 0 to 3% (1% ammoniumhydroxide:methanol):chloroform gradient over a thirty minute period.Fractions containing desired product were concentrated in vacuo to anoil. The oil was treated with chloroform and saturated with hydrogenchloride gas. This solution was concentrated in vacuo to afford 3.64 gof the title compound. 1.50 g of this material was taken up intosolution with tetrahydrofuran (20 ml), the solution was boiled down toapproximately 10 ml, additional tetrahydrofuran (20 ml) was added andthe crystals were collected by filtration. Crystals were dried in avacuum oven overnight at 60° C. to afford 1.27 g of the title compound.

Mass Spectrum(FDMS): m/z 508 (M−HCl).

¹H NMR (CDCl₃): δ8.24 (s, 2H), 7.71 (s, 1H), 7.53 (d, J=8.6 Hz, 2H),6.96 (d, J=8.6 Hz, 2H), 6.07 (s, 1H), 4.46 (t J=5.7 Hz, 2H), 4.08 (t,J=5.7 Hz, 2H), 3.66 (m, 4H), 3.39 (t, J=5.7 Hz, 2H), 2.87 (m, 2H), 2.58(m, 2H), 1.50 (s, 18H).

Elemental analysis for C₃₀H₄₁ClN₂O₃S: Calculated: C, 66.09; H, 7.58; N,5.14. Found: C, 66.36; H, 7.82; N, 4.85.

EXAMPLE 302-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(piperazin-1-yl-methyl)phenoxy)ethyl)oxazoledihydrochloride hydrate

2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(4-acetylpiperazin-1-yl-methyl)phenoxy)ethyl)oxazolehydrochloride prepared as described in Example 28 above (0.97 g, 1.82mmole) was dissolved in 4N hydrochloric acid and stirred for 1.5 hoursat 80° C. The reaction was then diluted with ethyl acetate andneutralized with saturated sodium bicarbonate. The organic layer wasextracted with brine, dried over sodium sulfate, evaporated to dryness,and chromatographed on silica gel using a methylenechloride/methanol/ammonium hydroxide gradient to give the free base(0.67 g, 75%). The free base (1.29 g, 2.62 mmol) was dissolved inmethylene chloride, treated with hydrogen chloride gas, and evaporatedto give desired product (1.35 g, 91%).

¹H NMR (CDCl₃) δ10.15 (bs, 1H), 9.95 (bs, 1H), 7.95 (s, 2H), 7.55 (m,3H), 6.95 (m, 2H), 5.7 (s, 1H), 4.4 (bs, 2H), 4.25 (bs, 2H), 4.0-3.8 (m,8H), 3.1 (bs, 2H), 1.5 (s, 18H);

FD MS 491 (M⁺−HCl);

Elemental analysis for C₃₀H₄₃Cl₂N₃O₃.1.4H₂O: Calculated: C, 61.09; H,7.83; N, 7.12. Found: C, 60.71; H, 7.43; N, 7.02.

EXAMPLE 312-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(imidazol-1-yl-methyl)phenoxy)ethyl)oxazolehydrochloride monohydrate

A. Preparation of N-p-methoxybenzylimidazole

To a stirred solution of imidazole (25.53 g, 375 mmole) in acetonitrile(625 ml) was added p-methoxybenzyl chloride (16.95 ml, 125 mmole). Thereaction was refluxed for 16 hours, evaporated to dryness, andredissolved in methylene chloride and saturated sodium bicarbonate. Theorganic layer was extracted with water twice. Standard acid/base workupgave N-p-methoxybenzylimidazole (16.3 g, 69%) which was used withoutfurther purification:

¹H NMR (CDCl₃) δ7.5 (bs, 1H), 7.1 (m, 3H), 6.9 (m, 3H), 5.0 (s, 2H), 3.8(s, 3H).

B. Preparation of N-p-hydroxybenzylimidazole

To a stirred solution of the compound of Step A (16.3 g, 86.1 mmole) inmethylene chloride (860 ml) cooled to 5° C., was added boron tribromide(32.6 ml, 344.4 mmole) dropwise over 15 minutes. After 2 hours at 5° C.,the reaction was quenched with methanol dropwise, evaporated to dryness,and redissolved in methanol, water, and methylene chloride. The pH wasadjusted to 8.4 with sodium hydroxide. The organic lever was dried oversodium sulfate and evaporated to dryness to giveN-p-hydroxybenzylimidazole (13.6 g, 91%) which was used without furtherpurification:

¹H NMR (DMSO-d₆) δ9.5 (bs, 1H), 7.7 (bs, 1H), 7.1 (m, 3H), 6.9 (bs, 1H),6.75 (d, J=9 Hz, 2H), 5.05 (s, 2H);

FD MS 174 (M⁺).

C. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(imidazol-1-ylmethyl)phenoxy)ethyl)oxazolehydrochloride monohydrate

Title compound was prepared from the compound of Example 1C (24.75 g,78.1 mmole) substantially in accordance with the procedure in Example 4Ausing the compound of Step B, (13.6 g, 78.1 mmole), andtriphenylphosphine (22.5 g, 85.9 mmole). The filtrate was extracted withwater and brine and the organic layer was dried over sodium sulfate,evaporated to dryness, chromatographed on silica gel using a methylenechloride-isopropanol gradient, and triturated with hot diethyl ether togive the free base (2.51 g, 7%). The free base was dissolved inmethylene chloride (65 ml), treated with-hydrogen chloride gas, andevaporated to give desired product (2.63 g, 97%):

¹H NMR (CDCl₃) δ9.5 (s, 1H), 8.0 (s, 2H), 7.6 (s, 1H), 7.3 (m, 3H), 7.1(s, 1H), 6.95 (d, J=9 Hz, 2H), 5.8 (s, 1H), 5.4 (s, 2H), 4.35 (t, J=7Hz, 2H), 3.2 (d, J=7 Hz, 2H), 1.5 (s, 18H);

FDMS 473 (M⁺−HCl);

Elemental analysis for C₂₉H₃₆ClN₃O₃.H₂O: Calculated: C, 65.96; H, 7.25;N, 7.96. Found: C, 65.75; H, 7.07; N, 8.09.

EXAMPLE 322-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4,5-dihydro-1H-imidazol-2-ylmethyl)phenoxy)ethyloxazolehydrochloride

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-cyanomethylphenoxy)ethyl)oxazole

To a suspension of the compound of Example 1C, 4-hydroxybenzyl cyanide,triphenylphosphine and 0.7M (mmole alcohol/ml tetrahydrofuran) reactionsolution was added diethylazodicarboxylate. After stirring at 24° C. forapproximately 24 hours, the reaction was concentrated in vacuo to abrown oil. Material was treated with chloroform (30 ml), triturated andthe insolubles were filtered and washed with chloroform (20 ml). Thefiltrate was concentrated in vacuo to an oil, treated with toluene andsubjected to preparatory chromatography. The material was eluted with 0to 10% methanol/toluene gradient over a thirty minute period. Fractionscontaining the desired product were concentrated in vacuo to afford12.18 g (88%) of the subtitled compound.

Mass Spectrum(FDMS:m/z 432 (M).

¹H NMR (DMSOd₆): d 7.91 (s, 1H), 7.72 (s, 2H), 7.52 (bs, 1H), 7.25 (d,J=8.6 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 4.24 (t, J=6.5 Hz, 2H), 3.93 (s,2H), 2.97 (t, J=6.5 Hz, 2H), 1.41 (s, 18H).

Elemental analysis for C₂₇H₃₂N₂O₃: Calculated: C, 74.97; H, 7.46; N,6.48. Found: C, 75.17; H, 7.41; N, 6.21.

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4,5-dihydro-1H-imidazol-2-ylmethyl)phenoxy)ethyloxazolehydrochloride

To a solution of the compound of Step A (24 mmole, 10.39 g) in ethanol(2 ml) and diethyl ether (50 ml) at −10° C. hydrogen chloride gas wasbubbled through over a thirty minute period. Reaction was maintained at0° C. After four days, the supernatant was decanted off then absoluteethanol (50 ml) and diethyl ether (50 ml) were added. The reaction wascooled to 0° C. then hydrogen chloride gas was passed through thesolution for approximately four hours. After stirring at 0° C. for fourhours, the reaction was concentrated in vacuo to a foam. Next, the foamwas taken up into absolute ethanol (50 ml) then treated with ethylenediamine (48 mmole, 2.88 g). The resulting suspension was refluxed forapproximately 32 hours, filtered hot and the insolubles washed withethanol (20 ml). The filtrate was concentrated in vacuo to an oil. Theoil was treated with chloroform (100 ml) and washed with saturatedsodium bicarbonate (2×50 ml) and brine (1×50 ml). Organics were driedover sodium sulfate, filtered and concentrated in vacuo, to afford 8.38g of a foam. Material was taken up into chloroform and chromatographed.The material was eluted with 10% (1% ammoniumhydroxide/methanol):chloroform gradient over a thirty minute period.Remainder of the material was eluted with 10% (1% ammoniumhydroxide/methanol):chloroform. Fractions containing the desired productwere concentrated in vacuo to a foam. Material was taken up intomethylene chloride (100 ml) and washed with saturated sodium bicarbonate(2×50 ml) and (1×50 ml). Organics were dried over sodium sulfate,filtered, then hydrogen chloride gas was passed through the solution.This solution was concentrated in vacuo to afford a foam. A portion ofthe foam (1.26 g) was treated with methylene chloride (20 ml) andisopropyl ether (10 ml) then boiled down to approximately 20 ml totalvolume. The turbid solution was cooled at −10° C. for approximately onehour then decanted. The remaining oil was concentrated in vacuo toafford 1.08 g of a foam.

Mass Spectrum(FDMS): m/z 476 (M⁺1).

¹H NMR (CdCl₃): δ7.85 (s, 2H), 7.55 (s, 1H), 7.47 (d, J=8.5 Hz, 2H),6.78 (d, J=8.5 Hz, 2H), 5.59 (s, 1H), 4.19 (t, J=6.4 Hz, 2H), 2.96 (s,2H), 3.80 (s, 4H), 3.04 (t, J=6.4 Hz, 2H), 1.46 (s, 18H).

Elemental analysis for C₂₉H₃₈ClN₃O₃.C₆H₁₄O: Calculated: C, 74.97; H,7.46; N, 6.48. Found: C, 75.17; H, 7.41; N, 6.21.

EXAMPLE 336-[2-[(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxazolyl]ethoxy]-1,2,3,4-tetrahydroisoquinolinehydrochloride

A. Preparation ofN-tert-butoxycarbonyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline

A suspension of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline oxalate (0.17mole, 40.04 g) in methanol (150 ml) and tetrahydrofuran (420 ml) wastreated with diisopropylethylamine (0.38 mole, 48.50 g) then with asolution of di-tert-butyl dicarbonate (0.13 mole, 27.30 g) intetrahydrofuran (10 ml). After stirring at room temperature forapproximately 4 hours, the material was treated with methylene chloride(500 ml), brine (250 ml) and 10% aqueous sodium sulfate (250 ml). Phaseswere separated, the organic phase was washed with 10% aqueous sodiumsulfate (3×250 ml), brine (1×250 ml) then dried over sodium sulfate,filtered and concentrated in vacuo to a solid. The material was treatedwith methylene chloride and chromatographed, eluting with 0 to 35%(ethyl acetate/hexane) gradient over a thirty minute period. Fractionscontaining the desired product were concentrated in vacuo to afford27.63 g (66%) of the subtitled compound.

Mass Spectrum(FDMS): m/z 249 (M), 148 (M−101).

¹H NMR (DMSOd₆): δ9.21 (s, 1H), 6.93 (d, 1H), 6.58 (dd, J=2.4, 8.1 Hz,1H), 6.53 (d, J=2.4 Hz, 1H), 4.36 (s, 2H), 3.48 (t, J=5.9 Hz, 2H), 2.66(t, J=5.9 Hz, 2H), 1.41 (s, 9H).

Elemental analysis for C₁₄H₁₉NO₃:

Calculated: C, 67.45; H, 7.68; N, 5.62.

Found: C, 67.74; H, 7.53; N, 5.59.

B. Preparation of6-[2-[(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxazolyl]ethoxy]-2-tert-butoxycarbonyl-1,2,3,4-tetrehydroisoquinoline.

The title compound was prepared substantially as described in Example 4Aexcept using the compound of Step A and 0.7M reaction solution. Atapproximately 3.8 hours, the reaction was concentrated in vacuo to anoil. The oil was treated with methylene chloride (10 ml) and theinsolubles were collected by filtration and washed with methylenechloride (10 ml). The filtrate was then treated with methylene chloride(25 ml), washed with 0.1N sodium hydroxide (3×50 ml) and 10% aqueoussodium sulfate (2×50 ml). Organics were concentrated in vacuo to a foam,treated with ethyl acetate and subjected to preparatory chromatography.The material was eluted with 10 to 40% (ethyl acetate/hexane) gradientover a thirty minute period. Fractions containing title compound werecombined, concentrated in vacuo, and chromatographed. Material waseluted with 10 to 25% acetone:hexane gradient over a thirty minuteperiod. Fractions containing desired product were concentrated in vacuoto afford 5.60 g (56%) of the subtitled compound as a foam.

Mass Spectrum(FDMS): m/z 548 (M).

¹H NMR (DMSOd₆): δ7.89 (s, 1H), 7.70 (s, 2H), 7.50 (s, 1H), 7.04 (d,2H), 6.77 (m, 3H), 4.39 (s, 2H), 4.21(t, 2H), 3.48 (m, 2H), 2.93 (t,2H), 2.70 (t, 2H), 1.39 (s, 27H).

C. Preparation of6-[2-[(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxazolyl]ethoxy]-1,2,3,4-tetrahydroisoquinolinehydrochloride

A solution of the compound of Step B (9.8 mmole, 5.60 g) in methylenechloride (33 ml) was treated with thiophenol (98.1 mmole, 10.81 g). Thereaction was cooled to −10° C. then treated with trifluoroacetic acid(98.1 mmole, 8.26 g). After approximately 1.5 hours, the reaction waswarmed to 24° C. After stirring 5.5 hours at 24° C., the reaction wasconcentrated in vacuo, treated with chloroform and chromatographed.Material was eluted with 0 to 10% (1% ammonium hydroxide/methanol):chloroform gradient over a fifteen minute period. Fractions containingdesired product were reduced in volume, washed with water (50 ml), driedover sodium sulfate, filtered and concentrated in vacuo to afford anoil. Material was taken up into chloroform, then saturated with hydrogenchloride gas. This solution was concentrated in vacuo to afford 2.40 gof the title compound. This material was recystallized from 3:1diisopropyl ether:methylene chloride to afford 760 mg of the titlecompound.

Mass Spectrum(ion spray MS): m/z 449 (M+1).

¹H NMR (DMSOd₆): δ7.91 (s, 1 H), 7.72 (s, 2H), 7.55 (s, 1H), 7.12 (d,J=8.6 Hz, 2H), 6.85 (m, 3H), 4.23 (t, J=6.5 Hz, 2H), 4.15 (m, 2H), 3.32(m, 2H), 2.96 (m, 4H), 1.41 (s, 18H).

EXAMPLE 346-[2-[(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxazolyl]ethoxy]isoquinolinehydrochloride monohydrate

Title compound was prepared from compound of Example 1C (19.1 mmole,6.07 g), triphenylphosphine (21.1 mmole, 5.52 g) and6-hydroxyisoquinoline (21.1 mmole, 3.07 g) in tetrahydrofuran (43 ml) at−10° C. (ice/acetone bath) was added diethylazodicarboxylate (21.1mmole, 3.67 g) over an eleven minute period. After the addition wascomplete, the reaction was stirred at room temperature. At approximately3.8 hours the reaction was concentrated in vacuo to an oil. The oil wastaken up into chloroform then chromatographed. Material was eluted with70-85% ethyl acetate/hexane gradient over a thirty minute period.Fractions containing desired product were combined, reduced in volumeand chromatographed. Material was eluted with 0-15% methanol/toluenegradient over a thirty minute period. Fractions containing desiredproduct were combined and concentrated in vacuo to a solid. The solidwas treated with chloroform (100 ml), hydrogen chloride gas was passedthrough the solution which was then concentrated in vacuo to a yellowfoam. The foam was triturated in diisopropyl ether (100 ml) thenfiltered. Insolubles were treated with toluene (100 ml), heated untilboiling, filtered hot, and washed with toluene (50 ml).

These insolubles were crystallized from methylene chloride. Crystalswere treated with chloroform (60 ml), and then with hydrogen chloridegas and concentrated in vacuo to a foam. Material was triturated intoluene (100 ml) and filtered and the insolubles were collected byfiltration to afford 1.38 g of product.

Mass Spectrum (ion spray): m/z 444 (M−HCl).

¹H NMR (DMSOd₆): δ9.71 (s, 1H), 8.56 (d, 1H), 8.44 (d, 1H), 8.28 (d,1H), 7.99 (s, 1H), 7.84 (d, 1H), 7.73 (s, 2H), 7.64 (dd, 1H), 7.56 (bs,1H), 4.56 (t, 2H), 3.13 (t, 2H), 1.41 (s, 18H).

Elemental analysis for C₂₈H₃₃ClN₂O₃.1.0H₂O: Calculated: C, 67.38; H,7.07; N, 5.61. Found: C, 67.60; H, 6.87; N, 5.35.

EXAMPLE 352-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(5-N-ethyl-N-methylaminomethylpyrid-2-yl-oxy)ethyl)oxazoledihydrochloride

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(5-formylpyrid-2-yl-oxy)ethyl)oxazole

The title compound was prepared substantially as described in Example 4except using 2-pyridone-5-carboxaldehyde. After stirring at 22° C. forapproximately 15.5 hours, the reaction was treated with water (2.1 eq.,870 51). stirred 10 minutes then concentrated in vacuo to afford a foam.The foam chromatographed, eluting with a gradient of 50 to 65% ethylacetate:hexane over a thirty minute period. Fractions containing titlecompound were combined and concentrated in vacuo to afford a purplesolid. The solid was treated with diethyl ether, triturated, stirredapproximately 4 hours then filtered. The filtrate was concentrated invacuo to afford a purple foam. The foam was chromatographed, elutingwith a gradient of 20 to 35% acetone:hexane over a thirty minute period.Fractions containing the title compound were combined and concentratedin vacuo to afford 2.28 g of the subtitled compound as a foam. Thismaterial was taken on to the next step without further purification.

Mass Spectrum (FDMS): m/z 422. (M).

1H NMR (CDCl₃): δ9.43 (s, 1H), 7.82 (s, 2H), 7.78 (m, 2H), 7.34 (s, 1H),6.59(d, J=10.3 Hz, 1H), 5.54 (s, 1H), 4.39 (t, J=6.4 Hz, 2H), 3.07 (t,J=6.4 Hz, 2H),1.49 (s, 18H).

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(5-N-ethyl-N-methylaminomethyl-pyrid-2-yl-oxy)ethyl)oxazoledihydrochloride

Title compound was prepared from the compound of Step A substantially inaccordance with the procedure in Example 11. The material waschromatographed, eluting with a gradient of 0 to 5% (1% ammoniumhydroxide:methanol):chloroform over a thirty minute period. Remainingfractions were eluted with 5% (1% ammoniumhydroxide:methanol):chloroform. Fractions containing the title compoundwere combined and concentrated in vacuo to afford an oil. The oil wastreated with chloroform then hydrogen chloride gas resulting incrystalline formation. Crystals were collected by filtration and washedwith chloroform affording 1.44 g. Material was recrystallized frommethanol:tetrahydrofuran to afford 1.25 g of the title compound.

mp (C):237-239

Mass Spectrum (FDMS): m/z 465. (M−2HCl).

1H NMR (DMSOd₆): δ10.73 (bs, 1H), 7.88 (s, 1H), 7.78 (d, J=2.3 Hz, 1H),7.64(dd, J=2.3, 9.4 Hz, 1H), 6.45 (d, J=9.4 Hz, 1H), 4.12 (t, J=6.9 Hz,2H), 3.97 (m,4H), 2.76-3.02 (m, 4H), 2.50 (s, 3H), 1.41 (s, 18H), 1.16(t, J=7.2 Hz, 3H).

Elemental analysis for C₂₈H₄₁Cl₂N₃O₃:

Calculated: C, 62.45; H, 7.67; N, 7.80.

Found: C,62.46; H, 7.71; N, 7.79.

EXAMPLE 362-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethylphenylthio)ethyl)oxazolehydrochloride monohydrate

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formylphenylthio)ethyl)oxazole

Subtitled compound was prepared by dissolving 3.84 g (14.6 mmole)triphenylphosphine, in 45 ml of tetrahydrofuran, chilling to −9° C. thenadding under nitrogen, 2.3 ml (14.6 mmole) diethylazodicarboxylate. Thereaction exothermed to −1° C. and was chilled again to −6° C. 4.64 g(14.6 mmole) of the compound of Example 1C was added. The deep redsolution was stirred 15 minutes when 2.22 g (16.1 mmole)4-mercaptobenzaldehyde (Tet. Lett. 25, (17), 1753-1756, 1984) was addedand the reaction was allowed to stir for 18 hours. The reaction wasstripped and chromatographed eluting with 10% to 50% ethylacetate/hexane gradient over 30 minutes. The appropriate fractions werebulked and stripped to give 3.48 g (54%) product which was used withoutfurther purification.

NMR (CDCl₃), δ1.46 (t, 3H, J=9 Hz), 1.50 (s, 18H), 2.64 (d, 2H, J=5 Hz),2.88-2.97 (m, 1H), 3.17 (t, 2H, J=9 Hz), 3.51 (t, 2H, J=9 Hz), 3.97-32(m, 2H), 6.05 (s, 1H), 7.46 (d, 2H, J=9 Hz), 7.56 (d, 2H, J=9 Hz), 7.65(s, 1H), 8.21 (s, 2H).

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethylphenylthio)ethyl)oxazolehydrochloride monohydrate

Methylethylamine 1.72 ml (20 mmole) and 5.92 ml (20 mmole) of titaniumtetraisopropoxide were dissolved in 45 ml of punctilious ethanol, withstirring, under nitrogen and stirred 1 hour. Compound of Step A (4.38 g,10 mmole), was added and the reaction was stirred for 3.5 hours. Sodiumborohydride (570 mg, 15 mmole) was added and the reaction was stirred anadditional 18 hours. Ammonia (16.3 ml, 2N) was added to give a thicksuspension followed by 104 ml of methylene chloride. Diatomaceous earth(13 g) was added and the mixture was stirred and filtered throughdiatomaceous earth. The filtrate was washed one time with brine anddried, stripped and chromatographed, eluting with methylenechloride/methanol/concentrated ammonia 90:5:0.5. The fractions werecombined, stripped of solvent, and dissolved in methylenechloride/isopropyl ether. Hydrogen chloride gas was bubbled in and thesolution was concentrated and triturated with isopropyl ether to give2.86 g (55%) of title product as a white foam.

FDMS−M⁺480;

Elemental analysis for C₂₉H₄₀N₂O₂S.HCl.H₂O

Calculated: C, 64.86; H, 8.11; N, 5.21

Found: C, 64.56; H, 8.37; N, 4.93.

NMR (CDCl₃), δ1.46 (t, 3H, J=9 Hz), 1.50 (s, 18H), 2.64 (d, 2H, J=5 Hz),2.88-2.97 (m, 1H), 3.17 (t, 2H, J=9 Hz), 3.51 (t, 2H, J=9 Hz), 3.97-32(m, 2H), 6.05 (s, 1H), 7.46 (d, 2H, J=9 Hz), 7.56 (d, 2H, J=9 Hz), 7.65(s, 1H), 8.21 (s, 2H)

EXAMPLE 372-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethylphenoxy)ethyl)-5-methyloxazolehydrochloride monohydrate

A. Preparation of ethyl 4-chloro-3-oxopentanoate

Potassium ethyl malonate, 34 g (200 mmole) (Organic Synthesis Coll. Vol.IV, p. 417), 23.75 g (250 mmole) magnesium chloride, and 44.5 ml (320mmole) triethylamine were suspended in 1.0 L acetonitrile, withstirring, under nitrogen. 2-Chloro-propionyl chloride, 9.7 ml (100mmole), was added and the mixture was stirred under nitrogen for 18hours. 100 ml of 5N hydrochloric acid, was added and the reaction wasstirred for 2 hours. Layers were separated and organics stripped to give21.09 g of crude product which was filtered through 300 ml silica,eluting with 20% ethyl acetate/hexane to give 10.37 g (58%) product.

NMR (CDCl3), δ1.27 (t, 3H, J=4 Hz), 1.62 (d, 3H, J=4 Hz), 3.72 (dd, 2H,J=42 Hz), 4.52 (q, 2H, J=4 Hz)

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-carbethoxymethyl-5-methyloxazole

Compound of example 1A, 6.6 g (26.5 mmole) and 10.3 g (57.7 mmole) ofthe compound of Step A were stirred together neat, at 140° C., undernitrogen, for a total of 6.5 hours. The reaction was cooled andchromatographed on 300 ml silica, eluting with 20%, then 50% ethylacetate/hexane to give 4.48 g (45%) product.

FDMS−M+=373

NMR (CDCl3), δ1.27 (t, 3H, J=4 Hz), 1.47 (s, 18H), 2.34 (s, 3H), 3.54(s, 2H), 4.18 (q, 2H, J=4 Hz), 5.46 (s, 1H), 7.78 (s, 2H)

C. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)-5-methyloxazole

Starting ester, the compound of Step B 4.43 g (11.88 mmole), wasdissolved in 83 ml tetrahydrofuran with stirring, under nitrogen. Solidlithium aluminum hydride (LAH), 450 mg (11.88 mmole), was cautiouslyadded. There was much bubbling. The mixture was stirred 30 minutes andanother 225 mg (5.94 mmole) lithium aluminum hydride was added and thereaction stirred under nitrogen overnight. Water (0.675 ml) wascautiously added followed by 0.675 ml 15% sodium hydroxide, followed by2.0 ml water. The inorganics were filtered off and the filtrate wasstripped, dissolved in ethyl acetate, washed once with 1 N hydrochloricacid, twice with brine, and stripped to give 3.61 g (92%) of productwhich was used without further purification.

FDMS−M+=331

NMR (CDCl3), δ1.48 (s, 18H), 2.32 (s, 3H), 2.73 (t, 2H, J=4 Hz), 3.91(t, 2H, J=4 Hz), 5.51 (s, 1H), 7.81 (s, 2H)

D. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formylphenoxy)ethyl)-5-methyloxazole

The compound of Step C 3.61 g (10.9 mmole), 1.53 g (12.5 mmole)4-hydroxybenzaldehyde, and 3.29 g (12.5 mmole) triphenylphosphine weredissolved in 30 ml tetrahydrofuran with stirring, under nitrogen. Thesolution was chilled to −5° C. and a solution of 1.97 ml (12.5 mmole)diethyldiazodicarboxylate in 10 ml. tetrahydrofuran was added over 10minutes, with stirring. The reaction exothermed to +3° C. The bath wasremoved and the reaction stirred under nitrogen for 3 days. The reactionwas stripped, dissolved in methylene chloride and placed in the freezer.The diethoxycarbonylhydrazine was then filtered off and the filtrate waschromatographed on 400 ml silica, eluting with a 5% isopropylalcohol/hexane. The appropriate fractions were bulked and stripped togive 3.52 g (74%) product which was used without further purification.

FDMS−M+=435.

NMR (CDCl3), δ1.48 (s, 18H), 2.37 (s, 3H), 3.01 (t, 2H, J=4 Hz), 4.34(t, 2H, J=4 Hz), 5.48(s, 1H), 7.00 (d, 2H, J=7 Hz), 7.80 (s, 2H), 7.82(d, 2H, J=7 Hz), 9.87 (s, 1H)

E. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethylphenoxy)ethyl)-5-methyloxazolehydrochloride hydrate

Methylethylamine, 0.71 ml (8.32 mmole) and 2.46 ml (8.32 mmole) Ti(OPr)4were dissolved in 17 ml of ethanol and stirred for 10 minutes undernitrogen. Compound of step D, 1.75 g (4.16 mmole), was added and themixture was stirred for 4 hours. Sodium borohydride, 240 mg (6.23 mmole)was added and the reaction was stirred for 3 days. Ammonia, 5.8 ml 2N,was added to give a thick suspension. Methylene chloride (40 ml) wasadded then 5.3 g diatomaceous earth and the mixture was stirred, andfiltered through diatomaceous earth. The filtrate was washed 2 timeswith brine then dried. The organics were stripped and chromatographed,eluting with methylene chloride/methanol/concentrated ammonia 90:10:1.Fractions were bulked, stripped, dissolved in methylenechloride/isopropyl ether. Hydrogen chloride gas was bubbled in. Productwas evaporate to dryness to give 1.36 g (63%) of a white foam.

FDMS−M+478;

Elemental Analysis for C₃₀H₄₂N₂O₃.HCl.H₂O Calculated: C, 67.58; H, 8.51;N, 5.25 Found: C, 67.21; H, 8.61; N, 5.06.

NMR (CDCl3), δ1.44 (t, 3H, J=4 Hz), 1.49 (m, 18H), 2.51 (s, 3H), 2.60(d, 2H, J=4 Hz), 2.88-3.23 (m, 4H), 3.99-4.14 (m, 2H), 4.43 (t, 2H, J=6Hz), 5.99 (s, 1H), 6.92 (d, 2H, J=7 Hz), 7.49 (d, 2H, J=7 Hz), 8.16 (s,2H)

EXAMPLE 382-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethylphenoxy)ethyl)thiazolehydrochloride hydrate

A. Preparation of N-methyl-(3,5-di-t-butyl-4-hydroxy)benzamide

(3,5-di-t-butyl-4-hydroxy)benzoic acid, 75 g (300 mmole) and 53.46 g(330 mmole) carbonyldiimidazole were refluxed in 900 ml tetrahydrofuran,with stirring, under nitrogen, for 2 hours. The reaction was cooled and300 ml 40% aqueous methylamine was added and stirred under nitrogen atroom temperature for 18 hours. The mixture was stripped to a wet solidand 500 ml of water was added. The mixture was stirred, and filtered togive 88.5 g (100%) product, which contained approximately 30 mole %imidazole. The product was used without further purification.

NMR (CDCl3), δ1.44 (s, 18H), 2.98 (d, 3H, J=4 Hz), 6.2 (bs, 1H), 7.58(s, 2H)

B. Preparation of N-methyl-(3,5-di-t-butyl-4-hydroxy)thiobenzamide

The compound of Step A 88.5 g (ca. 300 mmole), and 60.6 g (150 mmole)Lawessen's reagent was dissolved in 300 g hexamethylphosporamide at 100°C. and stirred under nitrogen at 100° C. for 1 hour. The mixture wascooled, water was added, and the mixture was extracted twice withdiethyl ether. The combined organic layers were washed three times withwater, and the organic layer was stripped to give 91.3 g of crudeproduct which was triturated with 250 ml methylene chloride to give 43.7g product. Hexane, 350 ml, was added to the filtrate with stirring togive a second crop of 26.7 g product. The filtrate was boiled down to400 ml to give a third crop of 7.2 g product. The total yield was 77.6 g(93%)

NMR (CDCl3), δ1.44 (s, 18H), 3.33 (d, 3H, J=4 Hz), 5.52 (bs, 1H), 7.60(s, 2H)

C. Preparation of 3,5-di-t-butyl-4-hydroxythiobenzoic acid,(3-ethoxycarbonyl-2-oxo-1-propionyl)ester

The compound of Step B 42.0 g (150 mmole), 27 ml (200 mmole) ethyl3-chloroacetoacetate and 24.9 g (150 mmole) potassium iodide was stirredin 1.0 l tetrahydrofuran, under nitrogen, and refluxed for 4.5 hours.The reaction was cooled and 75 ml water was added and the mixturestirred for 18 hours. The organics were stripped, and the crude productwas dissolved in chloroform, washed once with water, and once withbrine, then chromatographed, eluting with a gradient of methylenechloride to methylene chloride/methanol/concentrated ammonia, 90:10:1over 10 minutes. The partially purified product was then chromatographedon 600 ml silica, eluting with 10% ethyl acetate/hexane to give 28 g(44%) product.

FDMS−M+=394

NMR (CDCl3), δ1.25 (t, 3H, J=4 Hz), 1.45 (s, 18H), 3.66 (s, 2H), 3.98(s, 2H), 4.18 (q, 2H, J=4 Hz), 5.80 (s, 1H), 7.83 (s, 2H)

D. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-carbethoxymethylthiazole

The compound of Step C 25.1 g (63.7 mmole), and 19.6 g (255 mmole) ofammonium acetate was refluxed in 320 ml glacial acetic acid, withstirring, under nitrogen, for 3.25 hours. The reaction was cooled andethyl acetate and water were added. Layers were separated and theaqueous layer was washed once with ethyl acetate. The combined organiclayers were washed once with water and 8 times with saturated sodiumbicarbonate solution to achieve a final wash of pH 9. The organic layerwas stripped and the crude product chromatographed on 600 ml silica,eluting with 10% ethyl acetate/hexane to give 14.96 g (57%) product.

FDMS−M+=375.

NMR (CDCl3), δ1.29 (t, 3H, J=4 Hz), 1.48 (s, 18H), 3.87 (s, 2H), 4.21(q, 2H, J=4 Hz), 5.45 (s, 1H), 7.09 (s, 1H), 7.72 (s, 2H)

E. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)thiazole

The compound of Step D 5.0 g (13.33 mmole), was dissolved in 95 mltetrahydrofuran with stirring, under nitrogen. Solid lithium aluminumhydride, 760 mg (20 mmole), was cautiously added. There was muchbubbling. The mixture was stirred under nitrogen for 1 hour. Water, 0.76ml H₂O, was cautiously added followed by 0.76 ml 15% sodium hydroxide,followed by 2.3 ml water. The inorganics were filtered off and thefiltrate was stripped, dissolved in ethyl acetate, washed once with 1 Nhydrochloric acid, twice with brine, and stripped to give 4.42 g (99%)product which was used without further purification.

FDMS−M+=333

NMR (CDCl3), δ1.48 (s, 18H), 3.02 (t, 2H, J=4 Hz), 3.98 (t, 2H, J=4 Hz),5.50 (s, 1H), 6.87 (s, 1H), 7.73 (s, 2H)

F. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formylphenoxy)ethyl)thiazole

The compound of Step E 4.20 g (12.6 mmole), 1.76 g (14.44 mmole)4-hydroxybenzaldehyde, and 3.79 g (14.44 mmole) triphenyl phosphine weredissolved in 37 ml tetrahydrofuran with stirring, under nitrogen. Thesolution was chilled to −10° C. and a solution of 2.27 ml (14.44 mmole)diethylazodicarboxylate in 12.5 ml, tetrahydrofuran was added over 10minutes, with stirring. The reaction exothermed to −1° C. The bath wasremoved and the reaction stirred under nitrogen overnight. The reactionwas stripped, dissolved in methylene chloride and placed in the freezer.The diethoxycarbonylhydrazine was then filtered off and the filtrate waschromatographed on 400 ml silica, eluting with a 15 then 20% ethylacetate/hexane. The appropriate fractions were bulked and stripped togive 3.98 g (72%) product which was used without further purification.

NMR (CDCl3), δ1.48 (s, 18H), 3.31 (t, 2H, J=4 Hz), 4.45 (t, 2H, J=4 Hz),5.47 (s, 1H), 6.96 (s, 1H), 7.03 (d, 2H, J=7 Hz), 7.73 (s, 2H), 7.83 (d,2H, J=7 Hz), 9.88 (s, 1H)

G. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-methyl-N-ethylaminomethylphenoxy)ethyl)thiazolehydrochloride hydrate

N-methyl-N-ethylamine, 0.96 ml (11.26 mmole), and 3.33 ml (11.26 mmole)Ti(OPr)4 was dissolved in 20 ml of ethanol with stirring under nitrogen.The mixture was stirred for 10 minutes. The compound of Step F, 2.46 g(5.63 mmole) was added and the mixture was stirred for 2.5 hours. Sodiumborohydride, 320 mg (8.44 mmole), was added and the reaction was stirredfor 3.5 days. Ammonia, 7.85 ml 2N, was added to give a thick suspensionthen 55 ml of methylene chloride was added. Diatomaceous earth, 7.2 g,was added and the mixture was stirred and filtered through diatomaceousearth. The filtrate was washed twice with brine then dried and theorganics were stripped and chromatographed, eluting with methylenechloride/methanol/concentrated ammonia 90:10:1. Fractions were combined,stripped and dissolved in methylene chloride/isopropyl ether. Hydrogenchloride gas was bubbled in and the product was concentrated andtriturated with isopropyl ether to give 1.54 g (54%) white foam.

FDMS−M+480;

Elemental Analysis for C₂₉H₄₀N₂O₂S.HCl.1.75H₂O Calculated: C, 63.48; H,8.17; N, 5.11; Found: C, 63.55; H, 7.89; N, 4.86.

NMR (CDCl3), δ1.46 (t, 3H, J=4 Hz), 1.49 (m, 18H), 2.62 (d, 2H, J=4 Hz),2.89 (m, 1H, J=4 Hz), 3.15 (m, 1H), 3.50 (bs, 2H), 4.10 (m, 2H), 4.41(t, 2H, J=4 Hz), 5.75 (s, 1H), 6.96 (d, 2H, J=7 Hz), 7.12 (s, 1H), 7.50(d, 2H, J=7 Hz), 7.90 (s, 2H)

EXAMPLE 39E-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethylphenyl)-2-propenyl)oxazolehydrochloride hydrate

A. Preparation of4-(2-bromoethyl)-2-(3,5-di-t-butyl-4-hydroxyphenyl)oxazole

To a stirred solution of triphenylphosphine (31.0 g, 118 mmole) inmethylene chloride (394 ml) was added bromine (6.09 ml, 118 mmole). Asmall amount of additional triphenylphosphine was added to clear thesolution. To this was added a mixture of the compound of Example 1C(25.0 g, 78.9 mmole) and imidazole (10.7 g, 158 mmole) dissolved inmethylene chloride (315 ml) over 15 minutes. The reaction was allowed tostir at room temperature for 1 hour and was filtered. The filtrate wasevaporated to dryness, triturated with methylene chloride/toluene, andfiltered. This filtrate was chromatographed on silica gel using ahexane-ethyl acetate gradient to give the subtitled product (25.4 g,85%):

1H NMR (CDCl3) δ7.85 (s, 2H), 7.5 (s, 1H), 5.5 (s, 1H), 3.65 (t, J=6 Hz,2H), 3.15 (t, J=6 Hz, 2H), 1.5 (s, 18H);

FDMS 381 (M+).

B. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-triphenylphosphoniumethyl)oxazole bromide

To a stirred solution of4-(2-bromoethyl)-2-(3,5-di-t-butyl-4-hydroxyphenyl)oxazole (25.4 g, 66.8mmole) in xylenes (135 ml) was added triphenylphosphine (17.5 g, 66.8mmole). The reaction was heated to reflux for 22 hours, and the xylenedecanted from the precipitated product. The product was triturated indiethyl ether, filtered, and then triturated with ethyl acetate andfiltered to give the intermediate phosphonium salt2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-triphenylphosphoniumethyl)oxazole bromide (30.7 g, 72%):

1H NMR (CDCl3) δ8.2 (bs, 1H), 7.8 (m, 17H), 5.5 (bs, 1H), 4.2 (bs, 2H),3.1 (bs, 2H), 1.5 (s, 18H);

FDMS 562 (M−Br+).

C. Preparation ofE-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-formylphenyl)-2-propenyl)oxazolediethyl acetal

To a stirred solution of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-triphenylphosphoniumethyl)oxazole bromide (28.1 g, 43.8 mmole) in tetrahydrofuran (220 ml)was added terepthaldehyde mono-diethylacetal (8.68 ml, 43.8 mmole). Thismixture was cooled to −10° C. and a 1M solution of sodiumhexamethyldisilazane in tetrahydrofuran (87.5 ml, 87.5 mmole) was addeddropwise over 8 minutes maintaining a temperature of less than 4° C. Thereaction was stirred at 0° C. for 3 hours, quenched with water, anddiluted with ethyl acetate and water. The pH was adjusted to 8.5 with 1Nhydrochloric acid. The organic layer was extracted with brine, driedover sodium sulfate, evaporated to dryness, and chromatographed onsilica gel using a hexane/acetone gradient to give the trans isomer ofthe olefin intermediateE-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-formylphenyl)-2-propenyl)oxazolediethyl acetal (2.6 g, 12%):

1H NMR (CDCl3) 7.85 (s, 2H), 7.4 (m, 5H), 6.55 (d, J=16 Hz, 1H), 6.4(dt, J=16 Hz, 7 Hz, 1H), 5.5 (s, 1H), 5.45 (s, 1H), 3.5-3.6 (m, 6H), 1.5(s, 18H), 1.25 (t, J=6 Hz, 6H);

FDMS 491 (M+).

D. Preparation ofZ-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-formylphenyl)-2-propenyl)oxazolediethyl acetal

Impure fractions from the above chromatography were rechromatographed onsilica gel using a hexane-diethylether gradient to give the subtitledproduct (1.6 g, 7%):

1H NMR (CDCl3) 7.85 (s, 2H), 7.45 (d, J=8 Hz, 2H), 7.4 (s, 1H), 7.3 (d,J=8 Hz, 2H), 6.35 (d, J=11 Hz, 1H), 5.95 (dt, J=11 Hz, 7 Hz, 1H), 5.5(s, 2H), 3.5-3.7 (m, 6H), 1.5 (s, 18H), 1.25 (t, J=6 Hz, 6H).

D. Preparation ofE-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-formylphenyl)-2-propenyl)oxazole

To a stirred solution of theE-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-formylphenyl)-2-propenyl)oxazolediethyl acetal (2.53 g, 5.14 mmole) in diethyl ether (51 ml) was added1N hydrochloric acid (51 ml), then concentrated hydrochloric acid (5.1ml) The reaction was allowed to stir 18 hours, then basidified withsaturated sodium bicarbonate. The organic layer was extracted withbrine, dried over sodium sulfate, evaporated to dryness, andchromatographed on silica gel using a hexane-ethyl acetate gradient togive the desired product (1.19 g, 55%):

1H NMR (CDCl3) 9.95 (s, 1H), 7.9 (s, 2H), 7.85 (d, J=8 Hz, 2H), 7.5 (d,J=8 Hz, 2H), 7.45 (s, 1H), 6.6 (m, 2H), 5.5 (s, 1H), 3.6 (d, J=5 Hz,2H), 1.5 (s, 18H);

FDMS 417 (M+).

F. Preparation ofE-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethyl-phenyl)-2-propenyl)oxazolehydrochloride

To a stirred solution of ethylmethylamine hydrochloride (0.54 g, 5.7mmole) in ethanol (5.8 ml) was added triethylamine (0.79 ml, 5.7 mmole),titanium tetraisopropoxide (1.68 ml, 5.7 mmole), and finally theE-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-formylphenyl)-2-propenyl)oxazole(1.19 g, 2.85 mmole) in ethanol (7.1 ml). The reaction was stirred for4.5 hours, then sodium borohydride (0.16 g, 4.28 mmole) was added. After20 hours at room temperature, the reaction was poured into 20 ml 2Nammonium hydroxide and diluted with methylene chloride. The mixture wasfiltered though diatomaceous earth and the filtrate was extracted withbrine. The organic layer was dried over sodium sulfate, evaporated todryness, and chromatographed on silica gel using a methylenechloride-methanol gradient to give the free base (0.79 g, 60%). The freebase (0.79 g, 1.71 mmole) was dissolved in methylene chloride (17 ml),treated with hydrogen chloride gas, and evaporated to give desiredproduct (0.83 g, 98%):

1H NMR (CDCl3) δ7.9 (s, 2H), 7.55 (d, J=9 Hz, 2H), 7.5 (d, J=9 Hz, 2H),7.45 (s, 1H), 6.6 (d, J=16 Hz, 1H), 6.45 (dt, J=16 Hz, 7 Hz, 1H), 5.6(s, 1H), 4.15 (m, 2H), 3.6 (d, J=7 Hz, 2H), 3.2 (m, 1H), 2.9 (m, 1H),2.65 (d, J=5 Hz, 3H), 1.5 (m, 21H);

FDMS 460 (M+−HCl);

Elemental Analysis for C₃₀H₄₁ClN₂O₂.1.5H₂O: Calculated: 68.75; H, 8.46;N, 5.34. Found: C, 69.06; H, 8.30; N, 5.49.

EXAMPLE 40Z-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethylphenyl)-2-propenyl)oxazolehydrochloride monohydrate

A. Preparation ofZ-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-formylphenyl)-2-propenyl)oxazole

To a stirred solution of the compound of Example 39D (1.59 g, 3.23mmole) in diethyl ether (32 ml) was added 1N hydrochloric acid (32 ml),then concentrated hydrochloric acid (3.2 ml). The reaction was allowedto stir 30 minutes, then basidified with saturated sodium bicarbonate.The organic layer was extracted with brine, dried over sodium sulfate,evaporated to dryness, and chromatographed on silica gel using ahexane-ethyl acetate gradient to give the desired subtitled product(1.15 g, 85%):

1H NMR (CDCl3) 10.0 (s, 1H), 7.9 (d, J=8 Hz, 2H), 7.85 (s, 2H), 7.5 (d,J=8 Hz, 2H), 7.45 (s, 1H), 6.65 (d, J=11 Hz, 1H), 6.1 (dt, J=11 Hz, 7Hz, 1H), 5.5 (s, 1H), 3.65 (d, J=7 Hz, 2H), 1.5 (s, 18H);

FDMS 417 (M+).

B. Preparation ofZ-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethyl-phenyl)-2-propenyl)oxazolehydrochloride

To a stirred solution of ethylmethylamine hydrochloride (0.78 g, 8.18mmole) in ethanol (4.1 ml) was added triethylamine (1.14 ml, 8.18mmole), titanium tetraisopropoxide (2.42 ml, 8.18 mmole), and finallytheZ-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4(3-(4-formylphenyl)-2-propenyl)oxazole(1.71 g, 4.09 mmole) in ethanol (10 ml). The reaction was stirred for3.5 hours, then sodium borohydride (0.23 g, 6.14 mmole) was added. After18 hours at room temperature, the reaction was poured into 30 ml 2Nammonium hydroxide and diluted with methylene chloride. The mixture wasfiltered though diatomaceous earth and the filtrate was extracted withbrine. The organic layer was dried over sodium sulfate, evaporated todryness, and chromatographed on silica gel using a methylenechloride-methanol gradient to give the free base (1.63 g, 86%). The freebase (1.3 g, 2.82 mmole) was dissolved in methylene chloride (28 ml),treated with hydrogen chloride gas, and evaporated to give desiredproduct (1.40 g, 100%):

1H NMR (CDCl3) δ8.05 (s, 2H), 7.6 (d, J=9 Hz, 2H), 7.5 (s, 1H), 7.35 (d,J=9 Hz, 2H), 6.65 (d, J=11 Hz, 1H), 6.05 (dt, J=11 Hz, 7 Hz, 1H), 5.8(s, 1H), 4.15 (m, 2H), 3.75 (d, J=7 Hz, 2H), 3.2 (m, 1H), 2.95 (m, 1H),2.7 (d, J=5 Hz, 3H), 1.5 (m, 21H);

FDMS 460 (M+−HCl);

Elemental Analysis for C₃₀H₄₁ClN₂O₂H₂O: Calculated: 69.95; H, 8.41; N,5.44. Found: C, 70.08; H, 8.10; N, 5.61.

EXAMPLE 412-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethylphenyl)propyl)oxazolehydrochloride hydrate

To a stirred solution ofZ-2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethylphenyl)-2-propenyl)oxazole(1.2 g, 2.6 mmole) in toluene (26 ml) was added 5% palladium on carbon(0.12 g). The suspension was subjected to 1 atmosphere hydrogen for 5hours and filtered. The filtrate was evaporated to dryness andchromatographed on silica gel using a methylene chloride-methanolgradient to give the saturated free base (0.99 g, 82%). The free base(1.05 g, 2.27 mmole) was dissolved in methylene chloride (23 ml),treated with hydrogen chloride gas, evaporated, and triturated withdiisopropyl ether to give desired product (1.00 g, 88%):

1H NMR (CDCl₃) δ7.9 (s, 2H), 7.5 (d, J=9 Hz, 2H), 7.4 (s, 1H), 7.3 (d,J=9 Hz, 2H), 6.65 (d, J=11 Hz, 1H), 5.6 (s, 1H), 4.1 (m, 2H), 3.1 (m,1H), 2.9 (m, 1H), 2.7 (t, J=7 Hz, 2H), 2.65 (m, 5H), 2.05 (m, 2H), 1.5(m, 21H);

FDMS 462 (M+−HCl);

Elemental Analysis for C₃₀H₄₃ClN₂O₂.1.5H₂O: Calculated: 68.48; H, 8.81;N, 5.32. Found: C, 68.40; H, 8.63; N, 5.22.

EXAMPLE 422-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methyl-N-ethylaminomethyl)phenoxymethyl)oxazolehydrochloride

A. N-carbo(3,5-di-t-butyl-4-hydroxy)phenyl-DL-serine methyl ester

To a suspension of benzoic acid in tetrahydrofuran (165 ml) was added inportions over a 20 minute period, 1,1′-carbonyldiimidazole. Theresulting gold solution was stirred at 22° C. for twenty minutes thenadded dropwise to the solution described below.

To a suspension of DL-serine methyl ester in tetrahydrofuran (115 ml)was added diisopropyl ethyl amine followed by dimethyl formamide (70ml). The resulting colorless solution was stirred at 22° C. for one hourthen the activated benzoic acid derivative (described above) was added.The reaction was stirred at 22° C. for 5 days then concentrated in vacuoto an oil. The oil was treated with ethyl acetate (250 ml) and washedwith three times with 1:1 brine: 0.1N hydrochloric acid, and one timewith brine. The organics were dried over sodium chloride, warmed on asteam bath, filtered hot, and the filtrate was concentrated in vacuo toan oil. The oil was then treated with 1:1 hexane:ethyl acetate, reducedin volume on a steam bath to approximately 250 ml then sonicated. Themixture was cooled to −20° C. for approximately 2 hours resulting incrystal formation. Crystals were collected by filtration, washed with70% hexane:ethyl acetate to afford 49.13 g of the title compound Thefiltrate was concentrated in vacuo to an oil. The oil was treated with1:1 hexane:ethyl acetate then subjected to prepatory chromatographyeluting with 50 to 70% hexane:ethyl acetate over a thirty-minute period.Desired fractions containing title compound were combined andconcentrated in vacuo to an oil. The title compound was recrystallizedfrom diethyl ether:hexane to afford 11.32 g of the title compound. Atotal of 60.45 g (56%) of the title compound was isolated.

mp (° C.):108-109

Mass Spectrum (FDMS): m/z 351 (M).

1H NMR (CdCl3): δ7.65 (s, 2H), 6.99 (d, J=6.2 Hz, 1H), 5.60 (s, 1H),4.85 (dt, J=3.6 Hz, 1H), 4.06 (bs, 2H), 3.83 (s, 3H), 1.45 (s, 18H).

Elemental Analysis for C₁₉H₂₉NO₅: Calculated: C, 64.94; H, 8.32; N,3.99. Found: C, 65.20; H, 8.42; N, 4.22.

B.4-((RS)carbomethoxy)-2-(3,5-di-tert-butyl-4-hydroxyphenyl))-2-oxazoline

To a suspension of N-carbo(3,5-di-t-butyl-4-hydroxy)phenyl-DL-serinemethyl ester 0.17 mmole, 58.81 g) and imidazole (0.18 mole, 12.53 g) inacetonitrite (890 ml) at 22° C. was added triphenylphosphine (0.18 mole,48.28 g) followed by carbon tetrabromide (0.18 mmole, 61.05 g). Afterstirring 2.5 hours, the reaction was concentrated in vacuo to a foamthat contains crystalline material. The mixture was treated with ethylacetate:hexane (100 ml), then cooled to −20° C. The insolubles werecollected by filtration and discarded. The filtrate was subjected topreparatory chromatography, eluting with a gradient of 25 to 40% ethylacetate:hexane over a 30-minute period. Fractions containing the titlecompound plus a coeluting impurity were resubjected to prepatorychromatography, eluting with 15 to 35% ethyl acetate:hexane over 30minutes. Fractions containing the title compound were combined,concentrated in vacuo to afford 55.75 g (99%) of an oil that slowlycrystallizes.

mp (° C.):102-104

Mass Spectrum (FDMS): m/z 333 (M)

¹H NMR (CDCl₃): δ7.80 (s, 2H), 5.59 (s, 1H), 4.91 (dd, J=7.6, 10.4 Hz,1H), 4.73 (dd, J=7.6, 8.6 Hz, 1H), 4.53 (dd, J=8.6, 10.4 Hz, 1H), 3.80(s, 3H), 1.45 (s, 18H)

Elemental analysis for C₁₉H₂₇NO₄: Calculated: C, 68.44; H, 8.16; N, 4.20Found: C, 68.33; H, 8.10; N, 4.34.

C. 4-(carbomethoxy)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazole

A solution of((RS)-4-carbomethyoxy)-2-(3,5-di-tert-butyl-4-hydroxypentyl))-2-oxazoline(0.66 mole, 220.15 g) in acetone (2.6 L) was treated with activatedmanganese oxide (6.60 mole. 574.0 g). The suspension was stirred at 22°C. for 17.5 hours then heated at 45° C. for one hour. Diatomaceous earth(250 ml) was added to the reaction, then the suspension was filteredthrough a pad of silica (2.5 cm×14.5 cm) and diatomaceous earth (250 g).The insolubles were rinsed with acetone until no product was observed inthe filtrate by thin layer chromatography. The filtrate was concentratedin vacuo to afford 303.5 g of a black solid. The material was treatedwith diethyl ether (500 ml), and placed on a steam bath until the soliddissolved, then hexane was added (250 ml). The solution was boiled downuntil crystals formed. The mixture was cooled to 22° C., crystals werecollected by filtration and washed with 2:1 hexane:diethyl ether toafford 98.1 g of the title compound that contains an impurity. Thismaterial was subjected to multi-recrystallizations as described above toafford 92.46 g of the title compound. Additional title compound wasisolated by multiple recrystallizations of the filtrates to afford 36.94g.

The filtrate from the crystallization was concentrated in vacuo to asolid then recrystallized as described above to afford 43.46 g of thetitle compound. The filtrate was concentrated in vacuo to a solid. Thesolid was treated with methylene chloride then divided into two lots.Each lot was subjected to preparatory chromatography eluting with 5 to25% ethyl acetate:hexane over a 30-minute period. Fractions containingthe title compound plus a coeluting impurity were combined andconcentrated in vacuo to afford a black solid. This solid wasrecrystallized as described above to afford 20.74 g of a yellow/greensolid. The solid was then triterated in boiling 1:4 ethyl acetate:hexane(200 ml), filtered hot and washed with 1:4 ethyl acetate:hexane toafford 17.99 g of the title compound. Additional title compound wasrecrystallized from the filtrate to afford 0.65 g. A total of 148.04 g(68%) of the title compound was isolated.

mp (° C.): 163

Mass Spectrum (FDMS): m/z 331 (M).

¹H NMR (CDCl₃): δ8.23 (s, 1H), 7.91 (s, 2H), 5.59 (s, 1H), 3.94 (s, 3H),1.48 (s, 18H).

Elemental Analysis for C₁₉H₂₅NO₄: Calculated: C, 68.86; H, 7.60; N,4.23. Found: C, 69.11; H, 7.72; N, 4.21.

D. (4-(hydroxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl))-2-oxazole

A dark blue solution of4-(carbomethoxy)-2-(3,5-di-tert-butyl-4-hydroxyphenyl))-2-oxazole (0.39mole, 127.71 g) in tetrahydrofuran (2.6 L) and a 3 neck 12 L flask wastreated with methanol (0.58 mole, 23.4 ml). Next, lithium borohydride(0.58 mole, 12.59 g) was added carefully over a 60 minute period. Duringthis addition, the reaction was cooled with an ice bath to maintaintemperature between 19 and 24° C. Once the borohydride addition wascomplete, the orange colored reaction was slowly bought to reflux (ca.50 minutes). After refluxing for 4.5 hours, the bright yellow coloredreaction was cooled to 22° C. The reaction was then carefully treatedwith 5N hydrochloric acid (620 ml) over a thirty-minute period. Vigorousgas evolution was observed during the addition of the first 40 ml ofhydrochloric acid. Ethyl acetate (1 L) was added and the reaction wasdivided into two lots. Each lot was treated with water (500 ml) and thephases were separated. The aqueous phases were combined and extractedtwice with ethyl acetate. The organic phases were combined andconcentrated in vacuo to an oil. Diethyl ether (500 ml) was added to theoil, reduced in volume on a steam bath to approx. 500 ml, then cooled to−78° C. (using dry ice/acetone) for one hour. After warming to 22° C.the resulting crystals were collected by filtration and washed withdiethyl ether to afford 56.55 g of the title compound. Subsequentrecrystallizations of the filtrate afforded an additional 52.76 g. Atotal of 109.31 g (94%) of the title compound was isolated.

mp (° C.):150

Mass Spectrum (FDMS): m/z 303 (M).

1H NMR (CdCL3): δ8.33 (s, 2H), 7.68 (s, 1H), 6.12 (s, 1H), 4.80 (s, 2H),1.51 (s, 18H).

Elemental Analysis for C₁₈H₂₅NO₃: Calculated: C, 71.26; H, 8.31; N,4.62. Found: C, 71.52; H, 8.26; N, 4.79.

E. 4-(bromomethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazole

A suspension of4-(hydroxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazole (44.2mmole, 13.41 g) in acetonitrile (230 ml) was treated withtriphenylphosphine (53.0 mmole, 13.91 g) followed by carbon tetrabromide(53.0 mmole, 17.59 g). The resulting solution was stirred atapproximately 22° C. for 3 hours. Next, additional carbon tetrabromide(22.0 mmole, 13.13 g) and triphenylphosphine 22.0 mmole, 5.79 g) wasadded to the reaction. After stirring for an additional 40 minutes, thereaction was quenched with water (5 mL), stirred 10 minutes andconcentrated in vacuo and stored at 5° C. for approximately 16 hours.The material was then taken up into chloroform and subjected toprepatory chromatography eluting with 35 to 50% chloroform:hexane over athirty-minute period. Fractions containing title compound were combined,dried over sodium sulfate, filtered, concentrated in vacuo to afford 9.7g of the title compound that crystallized out upon standing at 22° C.

mp (° C.):

Mass Spectrum (FDMS): m/z 367 (M+1).

1H NMR (CdCL3): δ7.84 (s, 2H), 7.65 (s, 1H), 5.53 (s, 1H), 4.44 (s, 2H),1.48 (s, 18H).

Elemental Analysis for: C₁₈H₂₄BrNO₂ Calculated: C, 59.02; H, 6.60; N,3.82. Found: C, 58.83; H, 6.53; N, 3.85.

F. 4-(4-(2-formyl)phenoxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl))oxazole

A suspension of4-(hydroxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazole (26.5mmole, 9.70 g), 4-hydroxybenzaldehyde (79.1 mmole, 3.56 g), potassiumcarbonate (79.4 mmole, 10.97 g) and potassium iodide (26.5 mmole, 4.39g) in methyl ethyl ketone (275 ml) was refluxed for 2 hours. Thereaction was then cooled to approximately 22° C., filtered, concentratedin vacuo to an oil. The oil was treated with ethyl acetate (250 ml) thenwashed twice with saturated aqueous sodium bicarbonate, once withaqueous sodiumbisulfate and once with brine. The organic layer was driedover sodium sulfate, filtered, and concentrated in vacuo to an oil. Thematerial was taken up into ethyl acetate, then subjected to prepatorychromatography eluting with 30 to 50 ethyl acetate:hexane over athirty-minute period. Fractions containing title compound plusimpurities were resubjected to prepatory chromatography eluting with 25to 35% acetone:hexane over a thirty-minute period. Fractions containingtitle compound were combined and concentrated in vacuo to afford 8.9 g(82%).

mp 160 (° C.):

Mass Spectrum (FDMS): m/z

1H NMR (CdCL3): δ9.90 (s, 1H),7.85 (d, 4H), 7.69 (s,1H), 7.12 (d, 2H),5.54 (s, 1H), 5.14 (s, 2H), 1.49 (s, 18H).

Elemental Analysis for: C₂₅H₂₉N₄ Calculated: C, 73.69; H, 7.17; N, 3.44.Found: C, 73.72; H, 7.16; N, 3.45.

G. 2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methylethylaminomethyl)phenoxymethyl)oxazole hydrochloride

The title compound was prepared substantially as described in Example11, except using 4-(4-(2-formyl)phenoxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)) andN-methyl-n-ethylamine. The crude material was subjected to prepatorychromatography eluting with 0 to 10% (methanol:ammoniumhydroxide):chloroform over a 30-minute period. Fractions containingtitle compound were combined and concentrated in vacuo to afford 6.0 g.The material was dissolved in diethyl ether (100 ml) then saturated withhydrochloric gas. The resulting precipatae was collected by filtrationand washed with diethyl ether. This material was dissolved in methylenechloride (50 ml) and washed with 0.1N ammoniumhydroxide (50 ml). Theorganic layer was dried over sodium sulfate then filtered. The filtratewas subjected to preparatory chromatography eluting with 0 to 10%(methanol:ammonium hydroxide):chloroform. Fractions containing titlecompound combined, concentrated in vacuo to a foam. The foam was treatedwith diethyl ether (100 ml) and saturated aqueous sodium bicarbonate(100 ml). The phases were separated, aqueous phase extracted withdiethyl ether (1×50 ml). The organic phases were combined, dried oversodium sulfate, filtered, then slowly added to a saturated solution ofhydrogen chloride diethyl ether. The resulting suspension wasconcentrated in vacuo to afford 4.74 g of the title compound as a foam.

Mass spectrum (FDMS): m/z 450 (M−HCl)

¹H NMR (CDCl₃): δ7.86 (s, 2H), 7.68 (s, 1H), 7.52 (d, J=8.6 Hz, 2H) 7.06(d, J=8.6 Hz, 2H), 5.54 (s, 1H), 5.07 (s, 2H), 4.10 (M, 2H), 3.17 (m,1H), 2.91 (m, 1H), 2.64 (d, J=5.0 Hz, 3H), 1.48 (m, 21H)

Elemental Analysis for: C₂₈H₃₉ClN₂O₃ Calculated: C, 69.05; H, 8.07; N,5.75 Found: C, 68.95; H, 7.98; N, 5.76.

EXAMPLE 432-(3,5-di-t-butyl-4-hydroxyphenyl)-4-((4-N-ethyl-N-propylaminoethylphenoxy)methyl)oxazolehydrochloride

A.2-(3,5-di-t-butyl-4-hydroxyphenyl-4-((4-N-ethyl-N-propionylaminoethylphenoxy)methyl)oxazole

To a stirred solution of N-ethyl,N-propionyl tyramine (2.84 g, 12.83mmole) in tetrahydrofuran (32.1 ml) was added 60% sodium hydridedispersion (0.56 g, 14.11 mmole). After stirring for 10 minutes, thecompound of Example 42(E) (4.70 g, 12.83 mmole) was added. The reactionwas allowed to stir at room temperature for 5 hours, poured into ethylacetate, and extracted with 10% sodium sulfate, then brine. The organiclayer was dried over sodium sulfate, evaporated to dryness, andchromatographed on silica gel using a hexane-ethyl acetate gradient.Further chromatography on silica gel using toluene-acetone gradientsyielded the intermediate phenyl ether (2.10 g, 32%):

¹H NMR (CDCl₃) (2 rotamers) δ7.9 (s, 2H), 7.65 (s, 1H), 7.15 (d, J=9 Hz,1H), 7.1 (d, J=9 Hz, 1H), 6.95 (m, 2H), 5.55 (s, 1H), 5.05 (s, 2H),3.1-3.5 (m, 4H), 2.8 (m, 2H), 2.15-2.4 (m, 2H), 1.5 (m, 18H), 1.05-1.2(m, 6H).

B.2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-((4-ethylpropylaminoethylphenoxy)methyl)oxazolehydrochloride

To a stirred solution of the intermediate phenyl ether prepared above(1.87 g, 3.69 mmole) in tetrahydrofuran (55 ml), was added 2Mborane-dimethylsulfide in tetrahydrofuran (5.9 ml, 11.81 mmole). Thereaction was heated to reflux for 3 hours, and evaporated to dryness.After redissolving in methanol, 0.99M hydrochloric acid in methanol (5.0ml) was added. The reaction was heated to 60° C. for 18 hours. Aftercooling to room temperature, the pH was adjusted to 8.5 with 1N sodiumhydroxide, and the solvent was evaporated. The residue was dissolved inethyl acetate and saturated sodium bicarbonate. The organic layer waswashed with brine, dried over sodium sulfate, evaporated to dryness, andchromatographed on silica gel using a methylene chloride-methanolgradient to give the free base (1.20 g, 66%). The free base (1.31 g,2.66 mmole) was dissolved in methylene chloride (40 ml), treated withhydrochloric acid, and evaporated to give desired product (1.43 g,100%):

¹H NMR (CDCl₃) δ7.85 (s, 2H), 7.6 (s, 1H), 7.15 (d, J=9 Hz, 2H), 6.95(d, J=9 Hz, 2H), 5.55 (s, 1H), 5.05 (s, 2H), 3.1 (m, 6H), 2.95 (m, 2H),1.85 (m, 2H), 1.5 (m, 18H), 1.4 (t, J=7 Hz, 3H), 1.0 (t, J=7 Hz, 3H);

FD MS 492 (M⁺−HCl);

Elemental analysis for C₃₁H₄₅ClN₂O₃.0.6H₂O: Calculated: C, 68.96; H,8.62; N, 5.19. Found: C, 68.76; H, 7.40; N, 5.25.

EXAMPLE 442-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-N-methyl-N-ethylaminomethylphenyloxy)propyl)oxazole

A. 2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-hydroxypropyl)oxazole

To a stirred solution of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-formylethyl)oxazole (Example43C) (9.01 g, 27.3 mmole) in diethylether (270 ml) was added sodiumborohydride (1.03 g, 27.3 mmole) in water (90 ml). After stirring for 3days, the reaction mixture was poured into diethylether, and extractedwith 1N hydrochloric acid, then brine. The organic layer was dried oversodium sulfate and evaporated to dryness, to yield the intermediateprimary alcohol (9.2 g, 100%):

¹H NMR (CDCl₃) δ7.8 (s, 2H), 7.4 (s, 1H), 5.5 (s, 1H), 3.8 (m, 2H), 3.25(m, 1H), 2.7 (t, J=7 Hz, 2H), 1.9 (m, 2H), 1.5 (m, 18H); FD MS 331 (M⁺).

B.2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-formylphenyloxy)propyl)oxazole

To a stirred solution of the intermediate primary alcohol prepared above(9.1 g, 27.45 mmole) in tetrahydrofuran (82 ml) was added4-hydroxybenzaldehyde (3.68 g, 30.20 mmole) and triphenylphosphine (7.91g, 30.20 mmole). After cooling to −20° C., a solution ofdiethylazodicarboxylate (4.75 ml, 30.20 mmole) in tetrahydrofuran (27ml) was added dropwise over 30 minutes. The reaction was allowed to warmto room temperature and stir for 18 hours, at which time it was dilutedwith diethylester and extracted with water, 1N sodium hydroxide, andbrine. The organic layer was dried over sodium sulfate, evaporated todryness, and chromatographed on silica gel using a hexane-acetonegradient to give the intermediate aldehyde (7.7 g, 64%):

¹H NMR (CDCl₃) δ9.9 (s, 1H), 7.85 (d, J=9 Hz, 2H), 7.85 (s, 2H), 7.4 (s,1H), 7.0 (d, J=9 Hz, 1H), 5.55 (s, 1H), 4.15 (t, J=7 Hz, 2H), 2.8 (t,J=7 Hz, 2H), 2.2 (m, 2H), 1.5 (s, 18H);

FD MS 435 (M⁺).

C.2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-(4-methylethylaminomethyl-phenyloxy)propyl)oxazolehydrochloride

To a stirred solution of the intermediate aldehyde prepared above (2.8g, 6.43 mmole) in dichloroethane (22 ml), was added N-ethyl-N-methylamine (0.55 ml, 6.43 mmole) and sodium triacetoxyborohydride (3.81 g,18.0 mmole). After 20 hours, the reaction was quenched with saturatedsodium bicarbonate and diluted with ethyl acetate. The organic layer wasextracted with brine, dried over sodium carbonate, evaporated todryness, and chromatographed on silica gel using a methylenechloride-methanol gradient to give the free base (2.38 g, 77%). The freebase was dissolved in methylene chloride (70 ml), treated withhydrochloric acid, and evaporated to give desired product (2.4 g, 94%):

¹H NMR (CDCl₃) δ7.9 (s, 2H), 7.5 (d, J=9 Hz, 2H), 7.4 (s, 1H), 6.95 (d,J=9 Hz, 2H), 5.6 (s, 1H), 4.1 (m, 2H), 4.05 (t, J=7 Hz, 2H), 3.2 (m,1H), 2.9 (m, 1H), 2.8 (t, J=7 Hz, 2H), 2.6 (d, J=4 Hz, 3H), 2.2 (m, 2H),1.5 (s, 18H);

FD MS 478 (M⁺−HCl);

Elemental analysis for C₃₀H₄₃ClN₂O₃.0.5H₂O: Calculated: C, 68.75; H,8.46; N, 5.34. Found: C, 68.93; H, 8.34; N, 5.17.

EXAMPLE 452-(3,5-dimethoxy-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethyl-phenyloxy)ethyl)oxazole

A. 4-benzyloxy-3,5-dimethyoxybenzamide

To a stirred solution of 4-benzyloxy-3,5-dimethoxy benzoic acid (23.4 g,81.2 mmole) in tetrahydrofuran (325 ml) was added carbonyldiimidazole(14.46 g, 89.3 mmole). After refluxing for 2 hours, the reaction wasallowed to cool to room temperature and ammonium hydroxide (81 ml) wasadded. The reaction was allowed to stir at room temperature for 1.5hours, diluted with ethyl acetate, then acidified with 1N hydrochloricacid. The organic layer was extracted with saturated sodium bicarbonate,then brine. The organic layer was dried over sodium sulfate andevaporated to dryness, to yield the intermediate benzamide (22.8 g,98%):

¹H NMR (CDCl₃) δ7.45 (d, J=9 Hz, 2H) 7.35 (m, 3H), 7.0 (s, 2H), 6.0 (bs,2H), 5.05 (s, 2H), 3.85 (s, 6H);

FD MS 287 (M⁺).

B. 2-(4-benzyloxy-3,5-dimethyoxyphenyl)-4-(ethylacetate)oxazole

A stirred suspension of the intermediate benzamide (22.8 g, 79.35 mmole)in 4-chloroacetoactetate (47.6 ml, 352 mmole) was heated to 130° C. for2 hours with azeotropic removal of water The reaction was then pouredinto ethyl acetate and the resulting suspension was filtered. Thefiltrate was extracted with water, saturated sodium bicarbonate, 1Nhydrochloric acid, then brine. The organic layer was dried over sodiumsulfate, evaporated to dryness, and distilled to remove4-chloroacetoactetate. The distillation pot was triturated withmethylene chloride, filtered, and the filtrate was chromatographed onsilica gel using a hexane-ethyl acetate gradient to give theintermediate ethyl ester (11.7 g, 37%):

¹H NMR (CDCl₃) δ7.7 (s, 1H), 7.5 (d, J=9 Hz, 2H), 7.35 (m, 3H), 7.25 (s,2H), 5.1 (s, 2H), 4.2 (q, J=7 Hz, 2H), 3.85 (s, 6H), 3.65 (s, 2H), 1.3(t, J=7 Hz, 3H); MS 398 (M⁺+1).

C. 2-(4-benzyloxy-3,5-dimethoxyphenyl)-4-(2-hydroxyehtyl)oxazole

To a stirred solution of the intermediate ethyl ester (11.7 g, 29.44mmole) in tetrahydrofuran (200 ml) was added 1M lithium aluminum hydridein tetrahydrofuran (26.5 ml, 26.5 mmole) dropwise over 10 minutes. Afteran additional 30 minutes, the reaction was quenched with dropwiseaddition of water (1.0 ml), 15% sodium hydroxide (1.0 ml), then wateragain (3.0 ml). The insolubles were filtered and washed with ethylacetate. The filtrate was extracted with 1N hydrochloric acid, thenbrine. The organic layer was dried over sodium sulfate, evaporated todryness, and chromatographed on silica gel using a hexane-acetonegradient to give the intermediate primary alcohol (7.9 g, 76%):

¹H NMR (CDCl₃) δ7.5 (s, 1H), 7.45 (d, J=9 Hz, 2H), 7.35 (m, 3H), 7.25(s, 2H), 5.1 (s, 2H), 3.95 (m, 2H), 3.9 (s, 6H), 3.85 (m, 2H);

MS 355 (M⁺).

D.2-(4-benzyloxy-3,5-dimethoxyphenyl)-4-(2-(4-formylphenyloxy)ethyl)oxazole

To a stirred solution of the of the intermediate primary alcohol (7.9 g,22.22 mmole) an tetrahydrofuran (67 ml) was added 4-hydroxybenzaldehyde(2.98 g, 24.44 mmole) and triphenylphosphine (6.41 g, 24.44 mmole).After cooling to −20° C., a solution of diethylazodicarboxylate (3.85ml, 24.44 mmole) in tetrahydrofuran (22 ml) was added dropwise over 26min. The reaction was allowed to warm to room temperature and stir for18 hours, at which time it was diluted with diethylether and extractedwith water, 1N sodium hydroxide, and brine. The organic layer was driedover sodium sulfate, evaporated to dryness, and chromatographed onsilica gel using a methylene chloride-ethyl acetate gradient to give theintermediate aldehyde (7.9 g, 77%):

¹H NMR (CDCl₃) δ9.9 (s, 1H), 7.85 (d, J=9 Hz, 2H), 7.55 (s, 1H), 7.45(d, J=9 Hz, 2H), 7.3 (m, 3H), 7.25 (s, 2H), 7.0 (d, J=9 Hz, 2H), 5.1 (s,1H), 4.4 (t, J=7 Hz, 2H), 3.9 (s, 6H), 3.1 (t, J=7 Hz, 2H).

MS 460 (M⁺+1).

E.2-(4-benzyloxy-3,5-dimethoxyphenyl)-4-(2-(4-methylethylaminomethyl-phenyloxy)ethyl)oxazole

To a stirred solution of the intermediate aldehyde (5.3 g, 11.53 mmole)in dichloroethane (40 ml) was added ethyl, methyl amine (0.99 ml, 11.53mmole) and sodium triacetoxyborohydride (6.84 g, 32.26 mmole). After 20hours, the reaction was quenched with saturated sodium bicarbonate enddiluted with ethyl acetate. The organic layer was extracted with brine,dried over sodium sulfate, evaporated to dryness, and chromatographed onsilica gel using a methylene chloride-methanol gradient to give theintermediate benzyl amine (4.9 g, 84%):

¹H NMR (CDCl₃) δ7.65 (s, 1H), 7.5 (d, J=9 Hz, 2H), 7.35 (m, 3H), 7.25(s, 2H), 7.2 (d, J=9 Hz, 2H), 6.85 (d, J=9 Hz, 2H), 5.05 (s, 2H), 4.25(t, J=7 Hz, 2H), 3.9 (s, 6H), 3.4 (s, 2H), 3.1 (t, J=7 Hz, 2H), 2.45 (q,J=7 Hz, 2H), 2.2 (s, 3H), 1.1 (t, J=7 Hz, 3H);

MS 502 (M⁺).

F.2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethyl-phenyloxy)ethyl)oxazolehydrochloride

To a stirred solution of the intermediate benzyl amine prepared above(4.4 g, 8.75 mmole) in methanol (175 ml) was added concentratedhydrochloric acid (175 ml). The reaction was heated to 70° C. for 1hour, allowed to cool to room temperature, neutralised with sodiumbicarbonate, and extracted with ethyl acetate. The organic layer wasextracted with brine, dried over sodium sulfate, evaporated to dryness,and chromatographed on silica gel using a methylene chloride-methanolgradient to give the free base (2.8 g, 70%) The free base was dissolvedin methylene chloride (75 ml), treated with hydrochloric acid, andevaporated to give desired product (3.08 g, 100%):

¹H NMR (CDCl₃) δ7.6 (s, 1H), 7.55 (d, J=9 Hz, 2H), 7.4 (s, 2H), 6.95 (d,J=9 Hz, 2H), 4.35 (t, J=7 Hz, 2H), 4.1 (m, 2H), 3.95 (s, 6H), 3.15 (m,3H), 2.9 (m, 1H), 2.65 (d, J=4 Hz, 3H), 1.5 (t, J=7 Hz, 2H);

MS 413 (M⁺−HCl+1);

Elemental analysis for C₂₃H₂₉ClN₂O₅.1.5H₂O: Calculated: C, 57.98; H,6.94; N, 5.62. Found: C, 58.04; H, 6.78; N, 5.89.

EXAMPLE 462-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(2-methylthioethyl)methylaminomethyl-phenyloxy)ethyl)oxazolehydrochloride

To a stirred solution of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-2-(4-methyl)aminomethylphenyloxy)ethyl)oxazole (8.06 g, 18.48 mmole) in dimethylformamide(46 ml) was added 60% sodium hydride dispersion (1.77 g, 44.35 mole).After 20 minutes of stirring, 2-chloroethyl methyl sulfide (1.84 ml,18.48 mmole) was added. The reaction was heated to 80° C. for 7.5 hours,with more chloroethyl methyl sulfide (1.84 ml, 18.48 mmole) added at 2.5and 5 hours. The reaction was quenched with water and diluted with etherand saturated sodium bicarbonate. The aqueous layer was extracted withethyl acetate and the combined organics were extracted with brine. Theorganic layer was dried over sodium sulfate, evaporated to dryness, andchromatographed on silica gel using a hexane-acetone gradient to givethe free base (4.6 g, 46%). The free base (1.00 g, 1.96 mmole) wasdissolved in methylene chloride (20 ml), treated with hydrochloric acid,and evaporated to give desired product (1.09 g, 100%):

¹H NMR (CDCl₃) δ8.0 (s, 2H), 7.6 (s, 1H), 7.5 (d, J=9 Hz, 2H), 7.0 (d,J=9 Hz, 2H), 5.7 (s, 1H), 4.35 (t, J=7 Hz, 2H), 4.15 (m, 2H), 2.9-3.3(m, 6H), 2.65 (s, 3H), 2.15 (s, 3H), 1.5 (s, 18H);

FD MS 511 (M⁺−HCl+1);

Elemental analysis for C₃₀H₄₃ClN₂O₃S.0.7H₂O: Calculated: C, 64.37; H,7.99; N, 5.00. Found: C, 64.25; H, 7.83; N, 4.74.

EXAMPLE 472-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(2-methylthioethyl)methylaminomethyl-phenyloxy)ethyl)oxazole,S-oxide hydrochloride

To a stirred solution of the free base prepared for2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(2-methylthioethyl)methylaminomethylphenyloxy)ethyl)oxazole(1.8g, 3.52 mmole) in methylene chloride (18 ml) was added 55%m-chloroperbenzoic acid (1.11 g, 3.52 mmole) an methylene chloride 11ml) at 0° C. over 10 minutes. After stirring at 0° C. for 1.5 hours, thereaction was diluted with methylene chloride and extracted withsaturated sodium bicarbonate. The organic layer was extracted withbrine, dried over sodium sulfate, evaporated to dryness, andchromatographed on silica gel using a chloroform-ethanol gradient togive the free base (0.79 g, 43%). The free base (0.78 g, 1.46 mmole) wasdissolved in methylene chloride (15 ml), treated with hydrochloric acid,and evaporated to gave desired product (0.80 g, 96%):

¹H NMR (CDCl₃) δ7.9 (s, 2H), 7.5 (m, 3H), 7.0 (d, J=9 Hz, 2H), 5.6 (s,1H), 4.3 (t, J=7 Hz, 2H), 4.2 (m, 2H), 3.2-3.8 (m, 4H), 3.15 (t, J=7 Hz,2H), 2.7 (m, 6H), 1.5 (s, 18H); FD MS 526 (M⁺−HCl);

Elemental analysis for C₃₀H₄₃ClN₂O₄S.1.1H₂O: Calculated: C, 61.80; H,7.81; N, 4.80. Found: C, 61.55; H, 7.50; N, 4.55.

EXAMPLE 482-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-ethylpropylaminoethylphenoxy)ethyl)oxazole

A. N-ethyl,N-propionyl tyramine

To a stirred solution of carbonyldiimidazole (14.13 g, 87.12 mmole) intetrahydrofuran (109 ml) at 5° C., was added dropwise a solution ofpropionic acid (6.5 ml, 87.12 mmole) in tetrahydrofuran (73 ml) over 30minutes. After stirring for 20 minutes, N-ethyl tyramine (12.0 g, 72.6mmole) in tetrahydrofuran (73 ml) was added over 20 minutes. Thereaction was allowed to warm to room temperature and stir for 4 hours.Methanol (7.3 ml) was added and stirring was continued for 30 minutes.The reaction was worked up by diluting with ethyl acetate and extractingwith 1N hydrochloric acid, saturated sodium bicarbonate, then brine. Theorganic layer was dried over sodium sulfate, evaporated to dryness, andchromatographed on silica gel using a methylene chloride-methanolgradient to give N-ethyl,N-propionyl tyramine (6.95 g, 43%):

¹H NMR (CDCl₃) (2 rotamers) δ7.65 (bs, 0.5H), 7.25 (bs, 0.5H), 7.05 (d,J=9 Hz, 1H), 7.0 (d, J=9 Hz, 1H), 6.8 (d, J=9 Hz, 2H), 3.2-3.6 (m, 4H),2.8 (m, 2H), 2.4 (q, J=7 Hz, 1H), 2.05 (q, J=7 Hz, 1H), 1.0-1.2 (m, 6H);

FD MS 221 (M⁺).

B. 2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-N-ethyl-N-propionylaminoethylphenoxy)ethyl)oxazole

To a stirred solution of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole (5.51 g,17.38 mmole) in tetrahydrofuran (47 ml) was added N-ethyl,N-propionyltyramine (3.5 g, 15.8 mmole) and triphenylphosphine (4.55 g, 17.38mmole). After cooling to 0° C., a solution of diethylazodicarboxylate(2.73 ml, 17.38 mmole) in tetrahydrofuran (16 ml) was added dropwiseover 10 minutes. The reaction was allowed to warm to room temperatureand stir for 22 hours, evaporated, and triturated with methylenechloride (50 ml) and filtered The filtrate was chromatographed on silicagel twice using methylene chloride-ethyl acetate and hexane-acetonegradients to give the intermediate phenyl ether (2.95 g, 36%):

¹H NMR (CDCl₃) (2 rotamers) δ7.85 (s, 2H), 7.5 (s, 1H), 7.15 (d, J=9 Hz,1H), 7.05 (d, J=9 Hz, 1H), 6.9 (m, 2H), 5.5 (s, 1H), 4.25 (t, J=7 Hz,2H), 3.2-3.4 (m, 4H), 3.05 (t, J=7 Hz, 2H), 2.8 (m, 2H), 2.35 (q, J=7Hz, 1H), 2.15 (q, J=7 Hz, 1H), 1.5 (s, 18H), 1.05-1.2 (m, 6H);

FD MS 520 (M⁺).

C.2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-ethylpropylaminoethylphenoxy)ethyl)oxazole

To a stirred solution of lithium aluminum hydride (0.42 g, 10.98 mmole)in tetrahydrofuran (22 ml) at 0° C. was added sulfuric acid (0.30 ml,5.49 mmole) dropwise, maintaining temperature below 10° C. The reactionas allowed to warm to room temperature and stirred for 1 hour, beforerecooling to 0° C. The intermediate phenyl ether (2.86 g, 5.49 mmole) intetrahydrofuran (5.5 ml) was added dropwise maintaining the temperaturebelow 5° C. The reaction was stirred at 0° C. for 2.5 hours, thenquenched with water (11 μl). The reaction was diluted with methylenechloride and 5N hydrochloric acid. The aqueous layer was extracted withmethylene chloride twice. The combined organics were extracted withbrine, then saturated sodium bicarbonate, and dried over sodium sulfate.Chromatography on silica gel using a methylene chloride-methanolgradient gave the free base (1.12 g, 40%). The free base (1.12 g, 2.21mmole) was dissolved in methylene chloride (30 ml), treated withhydrochloric acid gas, and evaporated to give desired product (1.22 g,100%):

¹H NMR (CDCl₃) δ8.15 (s, 2H), 7.65 (s, 1H), 7.15 (d, J=9 Hz, 2H), 6.9(d, J=9 Hz, 2H), 5.9 (s, 1H), 4.35 (t, J=7 Hz, 2H), 3.3 (t, J=7 Hz, 2H),3.2 (m, 6H), 2.95 (m, 2H), 1.9 (m, 2H), 1.5 (m, 18H), 1.45 (t, J=7 Hz,3H), 1.0 (t, J=7 Hz, 3H);

FD MS 507 (M⁺−HCl+1);

Elemental analysis for C₃₂H₄₇ClN₂O₃.2.8H₂O: Calculated: C, 64.75; H,8.93; N, 4.72. Found: C, 64.86; H, 8.55; N, 4.70.

EXAMPLE 492-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-butylethylaminomethyl-phenyloxy)ethyl)oxazole

To a stirred suspension of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formyl-phenyloxy)ethyl)oxazole(5.0 g, 11.88 mmole) in methanol (59 ml) was added N-ethyl-N-butyl amine(16.2 ml, 119 mmole). After 30 minutes the pH was adjusted to 7 withacetic acid. After an additional 30 minutes sodium cyanoborohydride(0.75 g, 11.88 mmole) was added and the pH was adjusted to 6 with aceticacid. The mixture was stirred for 5.5 hours and the methanol wasevaporated. The resultant residue was dissolved in ethyl acetate andsaturated sodium bicarbonate. The organic layer was extracted withbrine, dried over sodium sulfate, evaporated to dryness, andchromatographed on silica gel using a methylene chloride-methanolgradient to give the free base (2.82 g, 47%;. The free base wasdissolved in methylene chloride (75 ml), treated with hydrochloric acid,and evaporated to cave desired product (2.88 g, 95%):

¹H NMR (CDCl₃) δ7.9 (s, 2H), 7.55 (s, 1H), 7.55 (d, J=9 Hz, 2H), 6.95(d, J=9 Hz, 2H), 5.6 (s, 1H), 4.3 (t, J=7 Hz, 2H), 4.1 (d, J=5 Hz, 2H),3.15 (m, 3H), 2.8-3.0 (m, 3H), 1.8 (m, 2H), 1.5 (s, 18H), 1.4 (t, J=7Hz, 3H), 1.3 (m, 2H), 0.9 (t, J=7 Hz, 3H);

FD MS 506 (M⁺−HCl);

Elemental analysis for C₃₂H₄₇ClN₂O₃.H₂O Calculated: C, 68.49; H, 8.80;N, 4.99. Found: C, 68.59; H, 8.77; N, 4.99.

EXAMPLE 502-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-ethyl,i-propylaminomethyl-phenyloxy)ethyl)oxazole

To a stirred solution of N-ethyl,N-isopropylamine (3.31 ml, 11.88 mmole)in ethanol (24 ml) was added titanium tetraisopropoxide (7.01 ml, 23.8mmole), then2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formylphenyloxy)ethyl)oxazole(5.0 g, 11.88 mmole) in ethanol (24 ml). The reaction was stirred for 5hours, then sodium borohydride (0.67 g, 17.8 mmole) was added. After 18hours at room temperature, the reaction was poured into 100 ml 2Nammonium hydroxide and diluted with methylene chloride. The mixture wasfiltered though celite and the filtrate was extracted with brine. Theorganic layer was dried over sodium sulfate, evaporated to dryness, andchromatographed on silica gel using a methylene chloride-methanolgradient to give the free base (2.30 g, 39%). The free base wasdissolved in methylene chloride (75 ml), treated with hydrochloric acid,and evaporated to gave desired product (2.28 g, 92%):

¹H NMR (CDCl₃) δ7.9 (s, 2H), 7.7 (d, J=9 Hz, 2H), 7.6 (s, 1H), 7.0 (d,J=9 Hz, 2H), 5.6 (s, 1H), 4.35 (t, J=7 Hz, 2H), 4.2 (m, 2H), 3.6 (m,1H), 3.2 (t, J=7 Hz, 2H), 3.0 (m, 2H), 1.2-1.6 (m, 27H);

FD MS 492 (M⁺−HCl);

Elemental analysis for C₃₃H₄₅ClN₂O₃.0.5H₂O: Calculated: C, 69.19; H,8.62; N, 5.21. Found: C, 69.05; H, 8.82; N, 5.24.

EXAMPLE 512-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-(2-methyloxyethyl)methylaminomethyl-phenyloxy)ethyl)oxzaole

To a stirred solution of 2-methoxyethylmethylamine (1.07 ml, 10 mmole)in ethanol (5 ml) was added titanium tetraisopropoxide (2.95 ml, 10mmole), then2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-formyl-phenyloxy)ethyl)oxazole(2.11 g, 5 mmole) in ethanol (7.5 ml). The reaction was stirred for 4hours, then sodium borohydride (0.28 g, 7.5 mmole) was added. After 21hours at room temperature, the reaction was poured into 35 ml 2Nammonium hydroxide and diluted with methylene chloride. The mixture wasfiltered though celite and the filtrate was extracted with brine. Theorganic layer was dried over sodium sulfate, evaporated to dryness, andchromatographed on silica gel using a methylene chloride-methanolgradient to give the free base (2.21 g, 89%). The free base wasdissolved in methylene chloride (45 ml), treated with hydrochloric acid,and evaporated to give desired product (2.28 g, 96%):

¹H NMR (CDCl₃) δ8.0 (s, 2H), 7.6 (s, 1H), 7.55 (d, J=9 Hz, 2H), 6.95 (d,J=9 Hz, 2H), 5.75 (s, 1H), 4.35 (t, J=⁷ Hz, 2H), 4.2 (m, 2H), 3.85-3.95(m, 2H), 3.4 (s, 3H), 3.0-3.3 (m, 4H), 2.7 (d, J=4 Hz, 3H), 1.5 (m,18H);

FD MS 494 (M⁺−HCl);

Elemental analysis for C₃₀H₄₃ClN₂O₄.H₂O: Calculated: C, 62.62; H, 8.26;N, 5.10. Found: C, 65.63; H, 8.01; N, 7.03.

EXAMPLE 522-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methyl-N-ethylaminoethyl)phenoxymethyl)oxazolehydrochloride

A. 2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-formyl-N-ethylaminoethyl)phenoxymethyl)oxazole

To a solution of N-formyl-N-ethyl-p-hydroxyphenethylamine (18.9 mmole,3.65 g) in tetrahydrofuran (47 ml), at room temperature was added 60%sodium hydride (20.8 mmole, 0.83 g). The resulting suspension wasstirred at room temperature for 10 minutes then the compound of Example42(E) (18.9 mmole, 6.92 g) was added directly. The reaction mixture wasstirred at room temperature for 5 hours then poured into a 1:1 mixtureof ethyl acetate (500 ml) and 10% aqueous sodium hydrogen sulfatesolution (500 ml). Phases separated and the organic phase was washedwith brine (500 ml). The organic layer was concentrated in vacuo to anoil. The oil was subjected to preparatory chromatography, eluting with15 to 25% acetone:hexane over a 30 minute period then 25 to 35%acetone:hexane over a twenty minute period. Fractions containing productwere combined, concentrated in vacuo to afford 3.2 g of a foam. Thismaterial was taken onto the next step without further purification.

B. 2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methyl-N-ethylaminoethyl)phenoxymethyl)oxazole hydrochloride

To a suspension of lithium aluminum hydride (13.4 mmole, 0.507 g) intetrahydrofuran (20 ml) at −10° C. (ice/acetone cooling bath), was addeddropwise concentrated sulfuric acid (6.7 mmole, 0.66 g). The reactionwas stirred at room temperature for 50 minutes When cooled to 0° C. andtreated with a solution of the compound of part A, above, (6.7 mmole,3.20 g) in tetrahydrofuran (5.0 ml) over a 30 minute period. Thesuspension was stirred at room temperature for approximately 4 hoursthen quenched with water (0.48 ml). The resulting heavy suspension wastreated with chloroform (100 ml), 5N hydrochloric acid (50 ml) and brine(20 ml). The phases were separated and the aqueous phase was extractedwith chloroform (3×50 ml). The organic layers were combined and washedwith saturated aqueous sodium bicarbonate (2×50 ml) then brine (1×200ml). The organic phase was dried over sodium sulfate, filtered andconcentrated in vacuo to afford 4.28 g of an oil. Material was thensubjected to preparatory chromatography eluting with 0 to 5%(methanol:1% ammonium hydroxide):chloroform over a thirty minute periodthen 5 to 10% (methanol:1% ammonium hydroxide):chloroform over a twentyminute period. Fractions containing desired compound were combined andconcentrated in vacuo to afford 1.76 g of an oil. The oil was treatedwith chloroform then hydrogen chloride gas was passed through thesolution. The solution was concentrated in vacuo to afford 1.76 g of afoam which was dried overnight in a vacuum oven at 60° C.

Mass Spectrum (FDMS): m/z

^(H) NMR (CDCl₃): d8.01 (s,2H),7.72 (s, 1H), 7.16 (d, 2H), 6.99 (d, 2H),5.77 (s, 1H), 3.16 (m, 7H), 2.78 (3H), 2.41 (m, 3H), 1.50 (21H).

Analysis Calculated for C₂₉H₄₁ClN₂O₃+0.3mole H₂O: Calculated: C, 68.77:H, 8.23: N, 5.53. Found: C, 68.60; H, 8.15; N, 5.43.

EXAMPLE 532-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-((RS)-(4N-ethyl-N-methylaminomethyl)phenoxymethyl)oxazoline

A. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-((RS)-hydroxymethyl)oxazoline

A suspension of lithium aluminum hydride (48 mmole, 1.82 g) intetrahydrofuran (121 ml) at −10° C. was added dropwise to a solution ofthe compound of Example 42(B) (24.0 mmole, 8.01 g) in tetrahydrofuran(15 ml). This mixture was stirred at room temperature for approximately3.5 hours then quenched with water (3.45 ml). Filter aid was added tothe reaction then the suspension was filtered through a pad of silica.The filtrate was dried over sodium sulfate, filtered and concentrated invacuo to afford 7.41 g of crude material. This material was subjected topreparatory chromatography, eluting with 80 to 100% ethyl acetate:hexaneover a thirty minute period. Fractions containing title compound werecombined, concentrated in vacuo to afford 3.47 g.

Mass Spectrum (FDMS): m/z 305 (M).

Elemental analysis for C₁₀H₂₇NO₃: Calculated: C, 70.79: H, 8.91: N,4.59. Found: C,70.65; H, 9.05; N, 4.56.

B.2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-((RS)-(4-formyl)phenoxymethyl)oxazoline

To a solution of the compound of part A above (10.0 mmole, 3.06 g),p-hydroxybenzaldehyde (11.0 mmole, 1.35 g) and triphenylphosphine (11.0mmole, 2.63 g) in tetrahydrofuran (18 ml) cooled to 0° C., was addeddropwise diethylazodicarboxylate (11.0 mmole, 1.74 g). The solution wasstirred at room temperature for 4.5 hours then concentrated in vacuo toan oil. The oil was treated with chloroform (4 ml) and the crystals werecollected by filtration. To the filtrate was added water (10 ml), the pHwas adjusted to 8.65 with 0.1N sodium hydroxide, and the phases wereseparated. The organic phase was washed with water (2×10 ml) and brine(1×10 ml). The organic phases were dried over sodium sulfate, filteredand concentrated in vacuo. This material was subjected to preparatorychromatography eluting with 40 to 60% ethyl acetate:hexane over a 30minute period. Fractions containing title compound were combined andconcentrated in vacuo to afford 2.38 g of a white solid.

Mass Spectrum (FDMS): m/z 409 (M).

¹H NMR (CdCl3): δ9.88 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.79 (s,2H), 7.03(d, J=8.7 Hz, 2H), 5.58 (s, 1H), 4.70 (m, 1H), 4.55 (m, 1H), 4.41 (m,1H), 4.33 (m, 1H), 4.01 (m, 1H), 1.46 (s, 18H.

C.2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-((RS)-(4N-ethyl-N-methylaminomethyl)phenoxymethyl)oxazoline

To a solution of N-methylethylamine (4.9 mmole, 2.00 g) in ethanol (9.ml) at room temperature was added titanium isopropoxide (9.8 mmole, 2.78g). This mixture was stirred at room temperature for five minutes thenthe compound of part B, above, (4.9 mmole, 2.00 g) was added directly.The suspension was stirred at room temperature for 8.6 hours then sodiumborohydride (7.3 mmole, 0.28 g) was added directly followed by theaddition of ethanol (16 ml). The reaction mixture was stirred at roomtemperature for approximately 96 hours then treated with aqueoussaturated ammonium hydroxide solution. The resulting heavy suspensionwas stirred for 10 minutes, filter aid was added along with water (25ml) then filtered through the filter aid. Insoluble material was washedwith methylene chloride and brine. The filtrate phases were separatedand the aqueous phases were extracted with methylene chloride (2×50 ml).The organic phases were combined, dried over sodium sulfate, filteredand concentrated in vacuo to afford 3.15 g of an oil. The oilcrystallized out and was triterated in 9:1 hexane:diethyl ether.Insolubles were collected by filtration. The material was subjected topreparatory chromatography. Product was eluted with 0 to 10%methanol:chloroform over a 30 minute period. Fractions containing titlecompound were combine and concentrated in vacuo to afford 889 mg. Thismaterial was taken up into chloroform (25 ml) and washed with aqueoussaturated sodium bicarbonate (2×10 ml) and brine (1×10 ml). The organicphase was dried over sodium sulfate, filtered and concentrated in vacuoto afford 720 mg.

This material was recrystallized from diethyl ether to afford 640 mg ofthe title compound. This material was dried in a vacuum oven overnightat 45° C.

Mass Spectrum (FDMS): m/z 453 (M+1).

¹H NMR (CdCl3): d7.79 (s,2H),7.26 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz,2H), 5.57(s,1H), 4.64 (m, 1H), 4.53 (m, 1H), 4.38 (m, 1H), 4.27 (m, 1H),3.90 (m, 1H), 3.60 (2H), 2.60 (2H), 2.30 (2H), 1.46 (s, 18H), 1.29 (3H).

Elemental analysis for C₂₈H₄₁ClN₂O₃: Calculated: C, 74.30: H, 8.91: N,6.19. Found: C,74.45; H, 9.10; N, 6.22.

EXAMPLE 542-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-((4-N-methyl-N-ethylaminomethyl)phenoxymethyl)benzoxazole

A. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methoxybenzoxazole

A solution of 2-hydroxy-5-methoxyanaline (36.9 mmole, 5.13 g), boricacid (36.9 mmole, 2.28 g) and 3,5-di-tert-butyl-4-hydroxybenzoic acid(36.9 mmole, 9.23 g) in xylene (550 ml) was refueled using a Dien Starktrap for approximately two days. The reaction mixture was thenconcentrated in vacuo to an oil. The oil was treated with ethyl acetate(200 ml) and washed with saturated aqueous sodium bicarbonate (3×200ml). The organic phase was dried over sodium sulfate, filtered, andconcentrated in vacuo to afford 15.96 g of a black oil. The material wassubjected to preparatory chromatography eluting with 15 to 30% ethylacetate:hexane over a 30 minute period. Fractions containing titlecompound were combined and concentrated in vacuo to afford 5.18 g of asolid.

Mass Spectrum (FDMS): m/z 353 (M).

¹H NMR (CdCl₃): d8.07 (s, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.5Hz, 1H), 6.90 (dd, J=8.8,2.5 Hz, 1H), 5.64 (s, 1H), 3.86 (s, 3H), 1.52(s, 18H).

Elemental analysis for C₂₂H₂₇NO₃: Calculated: C, 74.76: H, 7.70: N,3.96. Found: C,74.62; H, 7.57; N, 4.01.

B. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-hydroxybenzoxazole

A solution of the compound of part A, above, (14.7 mmole, 5.18 g) inmethylene chloride (26 ml) at −78° C. was treated with boron tribromideover a 5 minute period. The reaction was stirred at −72° C. for 45minutes then at −10° C. for one hour then recooled back down to −78° C.At this point, the reaction was quenched with acetone (3 ml), warmed to0° C. and saturated aqueous sodium bicarbonate (25 ml) was added.Additional saturated aqueous sodium bicarbonate (25 ml) was addedfollowed by ethyl acetate (250 ml). Phases were separated and theaqueous phase was extracted with ethyl acetate (100 ml). The combinedorganic phases were dried over sodium sulfate, filtered and concentratedin vacuo to afford 2.2 g of a solid. A solid precipitate developed whiledrying with sodium sulfate. This material was carefully separated fromthe sodium sulfate providing an additional 3.23 g of the title compound.

Mass Spectrum (FDMS): m/z 340 (M+1).

¹H NMR (DMSOd6): d7.94 (s, 2H), 7.75 (s, 1H), 7.52 (d, J=8.7 Hz, 1H),7.05 (d, J=2.4 Hz,1H), 6.78 (dd, J=8.7,2.4 Hz, 1H), 1.44 (s, 18H).

Elemental analysis for C21H25NO3 0.3mole H2O: Calculated: C, 73.14: H,7.48: N, 4.06. Found: C,73.04; H, 7.35; N, 4.00.

C. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-(4-formylphenoxy)benzoxazole

A suspension of the compound of part B, above, (14.6 mmole, 4.97 g),powdered potassium carbonate (29.3 mmole, 4.05 g), 4-bromobenzaldehyde(29.3 mmole, 5.42 g) and copper (I) iodide (0.7 mmole, 0.139 g) inpyridine (25 ml) was sonicated for approximately 4 hours thenconcentrated in vacuo and heated at 140° C. for approximately 17 hours.The reaction was then cooled to room temperature, ethyl acetate (100 ml)was added and the reaction was washed with water (3×100 ml) and 10%aqueous sodium hydrogen sulfate (2×100 ml). The organic phase was driedover sodium sulfate, filtered and concentrated in vacuo to afford 7.64 gof an oil. The material was subjected to preparatory chromatographyeluting with 10 to 25% acetone:hexane over a 30 minute period. Fractionscontaining title compound were combined, concentrated in vacuo and setaside. Fractions containing title compound plus impurity wererechromatographed eluting with 2 to 5% ethyl acetate:hexane for thefirst 12 fractions (fraction size approximately 250 ml) then theremainder was eluted with 10% acetone:hexane. Fractions containing titlecompound were combined along with fractions from the prior run andconcentrated in vacuo to afford 2.18 g of a solid. This material wastaken on to the next step without further purification.

Mass Spectrum (FDMS): m/z 443 (M).

¹H NMR (DMSOd6): δ9.93 (s, 1H), 7.99 (s, 2H), 7.93 (d, J=8.7 Hz, 2H),7.85 (d, J=7.8 Hz, 2H), 7.60(d, J=2.4 Hz,1H), 7.17 (dd, J=8.7,2.4 Hz,1H), 7.13 (d, J=8.7 Hz, 2H), 1.46 (s, 18H).

D.2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-((4-N-methyl-n-ethylaminomethyl)phenoxymethyl)benzoxazole

To a suspension of the compound of Part C, above (4.6 mmole, 2.06 g) inethanol (27.6 ml) was added N-ethyl-N-methylamine (9.3 mmole, 0.549 g)followed by titanium (IV)isopropoxide. After stirring at roomtemperature for 4 hours, sodium borohydride (7.0 mmole, 0.263 g) wasadded. This suspension was stirred at room temperature for approximately15.5 hours then quenched with 2N ammonium hydroxide (31 ml). Thesuspension was stirred for 15 minutes then filter aid was added andfiltered through a pad of filter aid. Insolubles were washed withchloroform (100 ml) and brine (100 ml). The phases separated, and theaqueous phase was extracted with chloroform (3×50 ml). The combinedorganic phases were concentrated in vacuo to an oil. The material wasthen subjected to preparatory chromatography eluting with 0 to 10%(methanol:1% ammonium hydroxide):chloroform over a thirty minute period.Fractions containing title compound were combined, dried over sodiumsulfate and filtered. The filtrate was saturated with hydrogen chloridegas. The solution was then concentrated in vacuo to a foam. The foam wasdried in a vacuum oven at 60° C. overnight to afford 0.766 g of thetitle compound.

Mass Spectrum (FDMS): m/z 486 (M−HCl).

¹H NMR (CdCl3): δ8.07 (s, 2H), 7.55 (dd, J=8.75,2.4 Hz,3H), 7.38 (d,J=2.5 Hz,1H), 7.03 (m, 3H), 5.69(s,1H), 4.12 (m, 2H), 3.20 (m, 1H), 2.94(m, 1H), 2.67 (d, J=5.0 Hz,3H), 1.52 (s, 21H).

EXAMPLE 552-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-ethyl-N-methylaminomethyl)phenoxyethyl)-1,3,5-oxadiazole

A.2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-(methoxyethyl)-1,3,5-oxadiazole

To a suspension of 3,5-di-tert-butyl-4-hydroxybenzoic acid (13.6 mmole,3.41 g) in xylene (3.3 ml) at room temperature was added thionylchloride. The suspension was heated at 45° C. for 140 minutes to removeexcess thionyl chloride. At this point the acid chloride derivative wastransferred to a drop addition funnel. This material was added over afive minute period to a solution of methoxyethylamidoxime (15.0 mmole,1.78 g) in pyridine (6.7 ml). After the addition was complete, thereaction was heated at 100° C. for one hour. The suspension wasconcentrated to an oil then heated at 130° C. for 1.5 hours. Thereaction was cooled to room temperature, methylene chloride and waterwere added and the phases were separated. The aqueous phase wasextracted with methylene chloride. The combined organic phases werewashed with saturated aqueous sodium bicarbonate (2×50 ml) and brine(1×50 ml). The organic phase was dried over sodium sulfate, filtered,and concentrated in vacuo to afford 4.4 g of an oil. The material wassubjected to preparatory chromatography eluting with 15% acetone:hexane.Fractions containing title compound were combined, concentrated in vacuoto afford 2.12 g. This material was taken onto the next step withoutfurther purification.

¹H NMR (CdCl3): δ7.94 (s, 2H), 5.71(s,1H), 3.83 (t, J=6.8 Hz, 2H), 3.39(s, 3H), 3.06 (t, J=6.8 Hz, 2H), 1.49 (s, 18H).

B.2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-(hydroxyethyl)-1,3,5-oxadiazole

To a solution of the compound of part A, above, (6.4 mmole, 2.12 g) inmethylene chloride (11.3 ml) cooled to 0° C., was added borontribromide(19.1 mmole, 4.79 g). The reaction was stirred 2.7 hours at 0° C. thenquenched with saturated aqueous sodium bicarbonate (10 ml). Water (10ml) and methylene chloride (10 ml) were added, phases were separated andthe aqueous phase was extracted with methlene chloride (1×25 ml) Thecombined organic phases were dried over sodium sulfate, filtered, andconcentrated in vacuo to afford 2.27 g of an oil. The material wassubjected to preparatory chromatography eluting with 20 to 35% ethylacetate:hexane over a 30 minute period. Fractions containing titlecompound were combined and concentrated in vacuo to afford 1.63 g of thetitle compound.

Mass Spectrum (ion spray MS): m/z 318 (M).

¹H NMR (CdCl3): d7.94 (s, 2H), 5.74(s,1H), 4.05 (t, J=5.8 Hz, 2H), 3.04(t, J=5.8 Hz, 2H), 2.73 (t, J=6.4 Hz, 1H), 1.48 (s, 18H).

Elemental analysis for C₁₈H₂₆N₂O₃: Calculated: C, 67.90: H, 8.23: N,8.80. Found: C,68.03; H, 8.27; N, 8.67.

C.2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-formylphenoxylethyl)-1,3,5-oxadiazole

To a solution of the compound of part B, above, (4.8 mmole, 1.49 g),triphenylphosphine (5.1 mmole, 1.35 g) and p-hydroxybenzaldehyde (5.1mmole, 0.629 g) in tetrahydrofuran (8.6 ml) at 0° C. was addeddiethylazodicarboxylate (5.1 mmole, 0.895 g). The reaction was stirredat room temperature for four days then concentrated in vacuo to an oil.The material was subjected to preparatory chromatography eluting with 20to 35% ethyl acetate:hexane over a 30 minute period. Fractionscontaining title compound plus p-hydroxybenzaldehyde were combined andconcentrated in vacuo to an oil. The oil was treated with ethyl acetate(50 ml) then washed with 10% aqueous potassium carbonate (3×50 ml) then10% aqueous sodium bisulfate (1×50 ml). The organic phase was dried oversodium sulfate, filtered, and concentrated in vacuo to afford 520 mg ofa foam. The material taken on to the next step without furtherpurification.

¹H NMR (CdCl3): δ9.88 (s,1H), 7.94 (s, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.07(d, J=8.7 Hz, 2H), 5.74(s,1H), 4.51 (t, 2H), 3.31 (t, 2H), 1.48 (s,18H).

D. 2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-ethyl-N-methylaminomethyl)phenoxyethyl)-1,3,5-oxadiazole

To a solution of the compound of part B, above, (1.1 mmole, 0.450 g) in1,2-dichloroethane (5 ml) was treated with sodium triacetoxyborane (1.1mmole, 0.063 g) followed by N-methyl-N-ethyl amine (1.1 mmole, 0.063 g).The reaction was stirred at room temperature for approximately 24 hoursthen quenched with aqueous sodium bicarbonate (25 ml). Ethyl acetate wasadded, stirred 15 minutes then the phases were separated. The organicswere washed with aqueous sodium bicarbonate (3×25 ml). The organic phasewas concentrated in vacuo to an oil. The material was then subjected topreparatory chromatography, eluting with 0 to 10% (methanol:1% ammoniumhydroxide):chloroform over a thirty minute period. Fractions containingtitle compound were combined, dried over sodium sulfate and filtered.The filtrate was saturated with hydrogen chloride gas. The solution wasthen concentrated in vacuo to a foam. The foam was dried in a vacuumoven at 60° C. overnight to afford the title compound.

Mass Spectrum (FDMS): m/z

¹H NMR (CdCl3): δ7.94 (s,2H),7.49 (d, 2H), 7.00 (d, 2H),5.73 (s, 1H),4.44 (t, 2H), 4.10 (m, 2H), 3.28 (t, 2H), 3.18 (m, 1H), 2.86 (m, 1H),2.63 (m, 3H), 1.58 (3H), 1.49 (s, 18H).

Elemental analysis for C28H40ClN3O3: Calculated: C, 66.98: H, 8.03: N,8.37. Found: C,66.86; H, 7.91; N, 8.27.

EXAMPLE 562-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methyl-N-ethylaminomethyl)-1,2,3,4-tetrahydronaphthyl-6-oxyethyl)oxazole hydrochloride

A.2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-carbomethoxymethyl)phenoxy)oxazole

To a solution of the compound of Example 1, part C, above, (31.2 mmole,10.14 g), 4-hydroxyphenyl acetate (35.1 mmole, 5.85 g) andtriphenylphosphine (35.1 mmole, 9.23 g) in tetrahydrofuran (56 ml) atroom temperature was added diethylazodicarboxylate (35.1 mmole, 6.13 g).The reaction was stirred overnight at room temperature before beingconcentrated in vacuo to an oil. The oil was treated with methylenechloride and filtered, and the filtrate was concentrated in vacuo to anoil. The material was subjected to preparatory chromatography, elutingwith 20 to 35% acetone:hexane over a 30 minute period. Fractionscontaining title compound were resubjected to chromatography, elutingwith 15 to 30% ethyl acetate:hexane over a 30 minute period. Fractionscontaining title compound were combined, and concentrated in vacuo toafford 12.07 g of an oil.

Mass Spectrum (FDMS): m/z 465 (M).

¹H NMR (DMSOd6): d7.92 (s,1H),7.73 (s, 2H), 7.52(s, 1H), 7.16 (d, J=8.7Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 4.22 (t, J=6.6 Hz, 2H), 3.59 (s, 5H),2.96 (t, J=6.6 Hz, 2H), 1.41 (s, 18H).

Elemental analysis for C₂₈H₃₅NO₅: Calculated: C, 72.23: H, 7.58: N,3.01. Found: C,72.47; H, 7.65; N, 3.10.

B.2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-ethanoate)phenoxy)oxazole

A suspension of the compound of part A, above (26 mmole, 12.07 g) andlithium hydroxide (78 mmole, 1.86 g) in tetrahydrofuran (87 ml) andwater (28 ml) was heated at 65° C. for 4.5 hours. The reaction was thencooled to room temperature and brine (25 ml) and ethyl acetate (25 ml)and hexane (25 ml) were added. The phases were separated and the organicphase was washed with 10% aqueous sodium hydrogen sulfate (1×50 ml) andbrine (1×50 ml). The organic phase was concentrated in vacuo thensubjected to preparatory chromatography, eluting with 0 to 10%methanol:methylene chloride over a 30 minute period. Fractionscontaining title compound were rechromtatographed eluting with 0 to 3%methanol:methylene chloride over a 30 minute period. Fractionscontaining title compound were combined, and concentrated in vacuo toafford 1.60 g of a foam.

Mass Spectrum (FDMS): m/z 452 (M+1).

¹H NMR (CdCl3): d7.82 (s,2H),7.49 (s, 1H), 7.17(d, 2H), 6.85 (d, 2H),5.50 (s,1H), 4.16 (t, 2H), 3.56 (s, 2H), 3.06 (t, 2H), 1.48 (s, 18H).

Elemental analysis for C27H33NO5: Calculated: C, 71.82: H, 7.37: N,3.10. Found: C,71.82; H, 7.46; N, 3.03.

C.6-[2-[(3,5-di-tert-butyl-4-hydroxyphenyl)-4-oxazolyl]-ethoxy]-tetralone

To a solution of the compound of part B, above (3.5 mmole, 1.59 g) inmethylene chloride (5 ml) and 1 drop dimethylformamide at roomtemperature, was added thionyl chloride (4.2 mmole, 0.50 g) Thissolution was heated at 45° C. for 2 hours then cooled to roomtemperature and concentrated in vacuo to a foam. To a suspension ofaluminum chloride (10.6 mmole, 1.41 g) in methylene chloride (24 ml) at−10° C. was added a solution of the acid chloride in methylene chloride(3 ml) over a three minute period. Next, ethylene gas was bubbledthrough the suspension for approximately 105 minutes. The reaction wasthen poured into ice/water (50 ml) with stirring. Phases were separated,and the organic phase was washed with 1N hydrochloric acid (2×50 ml) andbrine (1×100 ml). The organic phase was dried over sodium sulfate,filtered and concentrated in vacuo to afford 1.46 g of a foam. Thematerial was subjected to preparatory chromatography eluting with 20 to35% ethyl acetate:hexane over a 30 minute period. Fractions containingtitle compound were combined, and concentrated in vacuo to afford 680 mgof an oil.

Mass Spectrum (ion spray MS): m/z 462 (M+1).

¹H NMR (CdCl3): d7.83 (s,2H),7.50 (s, 1H), 7.04 (d, 1H), 6.82 (2H),5.49(s,1H), 4.28 (2H), 3.51 (2H), 3.03 (m, 4H), 2.55 (2H), 1.48 (s,18H).

Elemental analysis for C₂₉H₃₅NO₄: Calculated: C, 75.46: H, 7.64: N,3.03. Found: C,75.41; H, 7.39; N, 3.02.

D. 2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methyl-N-ethylaminomethyl)1,2,3,4-tetrahydronaphthyl-6-oxyethyl)oxazole hydrochloride

This compound was substantially prepared as described for in Example 55,part D.

Mass Spectrum (ion spray MS): m/z 505 (M+1).

¹H NMR (CdCl3): δ8.25 (s,2H),7.71 (s, 1H), 7.00 (1H), 6.71 (1H), 6.64(1H), 5.30 (s,1H), 4.39 (2H), 3.57 (m, 1H), 3.39 (2H), 3.11 (m, 6H),2.79 (3H), 1.53 (s, 18H).

EXAMPLE 572-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-keto-3-(4-methylethylaminomethyl-phenyl)propyl)oxazole

A. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-iodoethyl)oxazole

A solution of triphenylphosphine (118.8 mmole, 31.12 g), in methylenechloride (460 ml) was treated with iodine (approximately 30.17 g) untila dull yellow color persisted. The reaction stirred fifteen minutes,then a solution of2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole (79.2mmole, 25.10 g) and imidazole (158.3 g, 10.77 g) in methylene chloride(300 ml) was added over a ten minute period. At 3.0 hours the reactionwas concentrated in vacuo then taken up into methylene chloride andsubjected to flash silica gel filtration. Desired product was elutedwith 1:1 ethyl acetate:hexane, collecting 500 ml tractions. Desiredfractions were combined, washed with 1×250 ml 1N sodium thiosulfate and1×250 ml brine, dried over magnesium sulfate, filtered, and concentratedin vacuo to afford 32.53 g (96%) of the title compound.

Mass Spectrum (FDMS): m/z 427 (M).

¹H NMR (CdCl₃): d 7.90 (s, 2H), 7.52 (s, 1H), 5.60 (s, 1H), 3.50 (t,J=7.1 Hz,2H), 3.18 (t, J=7.1 Hz, 2H), 1.49 (s, 18H).

Elemental analysis calculated for C₁₉H₂₆INO₂: Calculated: C,53.40; H,6.13; N, 3.28. Found: C, 53.64; H, 6.06; N, 3.30.

B. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-cyanoethyl)oxazole

To a solution of sodium cyanide (84.5 mmole, 5.50 g) indimethylsulfoxide (120 ml) at 92° C. was added2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-iodoethyl)oxazole (70.4mmole, 30.08 g) via a powder addition funnel over an eightyfive minuteperiod. Approximately 1.5 hours later, the reaction was cooled to roomtemperature and treated with 1:1 ethyl acetate:hexane (250 ml) and 10%aqueous potassium carbonate (250 ml). Three distinct phases result. Thelowest phase was separated and discarded. The remaining phases wereseparated. The aqueous phase was extracted with 1:1 ethyl acetate:hexane(2×200 ml). Combined organic phases were dried over sodium chloride,filtered, reduced in volume and subjected to preparatory chromotography.The material was eluted with 10 to 30% ethyl acetate:hexane. Fractionscontaining the desired product were combined, dried over MgSO₄, filteredand concentrated in vacuo to afford 18.25 g (79%).

Mass Spectrum(FDMS): m/z 326 (M).

¹H NMR (CDCl₃): d 7.84 (s, 2H), 7.53 (s, 1H), 5.54 (s, 1H), 2.94 (t,J=7.1 Hz, 2H), 2.78 (t, J=7.1 Hz, 2H), 1.49 (s, 18H).

Elemental analysis calculated for C₂₀H₂₆N₂O₂: Calculated: C, 73.59; H.8.03; N, 8.58. Found: C, 73.37; H, 8.05; N, 8.53.

C. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-formylethyl)oxazole

A solution of2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-cyanoethyl)oxazole (52 mmole,16.99 g) in toluene (167 ml) at −60° C. was treated with a 1.0 molarsolution of diisobutylaluminum hydride in toluene (67.7 mmole, 67.7 ml)over an eight minute period. After stirring 15 minutes at −78° C., thedry ice/acetone bath was removed and the reaction was stirred at roomtemperature for 1.75 hours. Next, the reaction was treated with methanol(6.5 ml) then a saturated solution of ammonium chloride (650 ml). Afterstirring at room temperature for 1.5 hours, the reaction was treatedwith 50% sulfuric acid (v/v) until a biphasic solution resulted.Crystals that developed in biphasic solution were removed by filtration.Phases were separated, and the aqueous phase was extracted with ethylacetate (2×250 ml) The combined organics were washed with aqueoussaturated solution of sodium bicarbonate (1×250 ml) then brine (1×500ml). The organic phase was reduced to approximately 50 ml total volumeand subjected to preparatory chromatography. The material was elutedwith 0 to 10% methanol:toluene gradient. Fractions containing thedesired product were combined, dried over magnesium sulfate, filteredand concentrated in vacuo to afford 15.13 g (88%).

Mass Spectrum(FDMS): m/z 329 (M).

¹H NMR (DMSOd₆): d 9.74 (s, 1H), 7.82 (s, 1H), 7.71 (s, 2H), 7.52 (s,1H), 2.78 (s, 4H), 1.41 (s, 18H).

Elemental analysis calculated for C₂₀H₂₇NO₃: Calculated: C, 72.92; H,8.26; N. 4.28. Found: C, 71.40; H, 8.27; N, 4.23.

D.2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-hydroxy-3-(4-(1,3-dioxolan-2-yl-)phenyl)propyl)oxazole

To a −70° C. solution of 2-(4-bromophenyl)-1,3-dioxolane (21.67 g, 94.6mmole) in tetrahydrofuran (142 ml), was added 1.6M n-butyl lithium inhexane (59.1 ml, 94.6 mmole) dropwise over 25 min. The resultingsuspension was stirred for 2 hours at −70° C., at which time2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-formylethyl)oxazole (10.39 g,31.53 mmole) in tetrahydrofuran (43 ml) was added dropwise over 30 min.After 1.75 hours, the cooling bath was removed. At −35° C., the reactionwas quenched with saturated ammonium chloride and diluted with ethylacetate and 10% sodium bisulfate. The organic layer was extracted withbrine, dried (sodium sulfate), evaporated to dryness, andchromatographed on silica gel using a methylene chloride:ethyl acetategradient to give the protected aldehyde/alcohol (7.84 g, 51%): ¹NMR(CDCl₃) δ7.85 (s, 2H), 7.4 (m, 4H), 7.35 (s, 1H), 5.8 (s, 1H), 5.5 (s,1H), 4.85 (m, 1H), 4.1 (m, 4H), 3.7 (d, J=4 Hz, 1H), 2.65 (t, J=7 Hz,2H), 2.1 (m, 2H), 1.45 (s, 18H); FD MS 479 (M⁺).

E.2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-hydroxy-3-(4-formyl)phenyl)propyl)oxazole

To a stirred solution of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-hydroxy-3-(4-(1,3-dioxolan-2-yl-)phenyl)propyl)oxazole(7.84g, 16.34 mmole) in acetone (82 ml) and water (25 ml), was addedpyridinium p-toluene sulfonate (0.21 g, 0.82 mmole). The reaction wasrefluxed for 1.5 hours before the acetone was evaporated. The remainingaqueous suspension was extracted with ethyl acetate. The organic layerwas extracted with brine, dried (sodium sulfate), and evaporated todryness to give the aldehyde/alcohol intermediate (6.82 g, 96%):

Mass Spectrum(FDMS): m/z 435 (M).

¹H NMR (CdCl₃): d 9.98 (s, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.82 (s, 1H),7.70 (s, 2H), 7.59 (J=8.0 Hz, 2H), 7.50 (s, 1H), 5.53 (d, J=4.6 Hz, 1H),4.72 (m, 1H), 2.53 (m, 2H), 1.92 (m, 2H), 1.41 (s, 18H).

Elemental analysis calculated for C₂₇H₃₃NO₄: Calculated: C, 74.46; H,7.64; N, 3.22. Found: C, 74.22; H, 7.64; N, 2.96.

F.2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-hydroxy-3-(4-methylethylaminomethyl-phenyl)propyl)oxazole

To a solution of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-hydroxy-3-(4-formyl)phenyl)propyl)oxazole(11.9 mmole, 5.18 g) in methanol (50 ml) cooled to −10° C., was addedN-methylethylamine (118.9 mmole, 7.03 g) followed by acetic acid 118.9mmole, 7.14 g) while maintaining the temperature below 4° C. during theadditions. Next, sodium cyanoborohydride (12.5 mmole, 0.78 g) was addedthen stirred at room temperature for two days. The reaction was thenconcentrated in vacuo, treated with 1:1 ethyl acetate:hexane (50 ml),phases were separated, and the organics were washed with aqueoussaturated sodium bicarbonate (25 ml) followed by 10% aqueous sodiumbisulfate and finally with brine (25 ml). The organics were concentratedin vacuo, treated with chloroform and subjected to preparatorychromatography. The material was eluted with 0 to 10% (methanol:1%ammonium hydroxide):toluene gradient over a twenty minute period.Fractions containing desired product were concentrated in vacuo treatedwith chloroform, then hydrogen chloride gas. The solution wasconcentrated in vacuo to a foam. The foam was taken up into methylenechloride (20 ml), filtered through talc and washed with methylenechloride (10 ml). The filtrate was treated with diisopropyl ether (10ml). The solution was boiled down to approximately 10 ml resulting inmaterial gumming out of solution. The solvent was decanted off and thegummy material was concentrated in vacuo to afford the title compound asa foam (1.78 g, 29%).

Mass spectrum(ion spray): m/z 479 (M−HCl+1).

¹H NMR (CdCl₃): δ8.12 (s, 2H), 7.62 (s, 1H), 7.53 (d, J=8.1 Hz, 2H),7.46 (d, J=8.1 Hz, 2H), 5.93 (s, 1H), 4.88 (m, 1H), 4.14(m, 2H), 3.18(m, 1H), 2.95 (m,2H), 2.88 (m, 1H), 2.63 (d, J=4.8 Hz, 2H), 2.20 (m,2H), 1.41 (m, 21H).

Elemental analysis calculated for C₃₀H₄₃ClN₂O₃.1.5H₂O: Calculated: C,66.46; H, 8.55; N, 5.17. Found: C, 66.38; H, 8.57; N, 5.22.

G.2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(3-keto-3-(4-methylethylaminomethyl-phenyl)propyl)oxazole

To a stirred solution of oxalyl chloride (0.23 ml, 2.68 mmole) inmethylene chloride (6.1 ml) at 60° C., was added dropwise a solution ofdimethylsulfoxide (0.38 ml, 5.37 mmole) in methylene chloride (1.2 ml).After warming to −20° C., a solution of the compound of part F, above(1.17 g, 2.44 mmole) in methylene chloride (2.4 ml) was added while thetemperature was maintained between −20 and −25° C. After 30 minutes atthis temperature, triethylamine (1.7 ml, 12.2 mmole) was added dropwise.The reaction was allowed to warm to room temperature and diluted withwater. The aqueous layer was extracted with methylene chloride. Thecombined organic layers were extracted with brine, dried over sodiumsulfate, evaporated to dryness, and chromatographed on silica gel usinga methylene chloride-methanol gradient to give the free base (1.37 g,85%). The free base (0.67 g, 1.41 mmole) was dissolved in methylenechloride (20 ml), treated with hydrochloric acid, and evaporated to givethe desired product (0.71 g, 99%):

¹H NMR (CDCl₃) δ8.1 (m, 4H), 7.8 (d, J=9 Hz, 2H), 7.6 (s, 1H), 5.8 (s,1H), 4.2 (m, 2H), 3.65 (t, J=7 Hz, 2H), 3.2 (m, 3H), 2.95 (m, 1H), 2.65(s, 3H), 1.5 (m, 21H);

FD MS 476 (M⁺−HCl+1);

Elemental analysis for C₃₀H₄₁ClN₂O₃.1.3H₂O: Calculated: C, 67.16; H,8.19; N, 5.22. Found: C, 66.90; H, 7.75; N, 5.24.

EXAMPLE 582-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methyl-N-ethylaminoethyl)phenoxymethyl)oxazolehydrochloride

A. N-carbo(3,5-di-t-butyl-4-hydroxy)phenyl-DL-serine methyl ester

In a 250 ml flask d,l-serine methyl ester hydrochloride (5 g, 20 mmole)was slurried in 50 ml methylene chloride at room temperature.Triethylamine (11.15 ml, 80 mmole) was added all at once, and theresulting solution was stirred at room temperature for 1 hour. In aseparate 250 ml flask 3,5-di-tert-butyl-4-hydroxybenzoic acid wascombined with 2-chloro-4,6-dimethoxy-1,3,5-triazine in 100 ml methylenechloride. The resulting solution was cooled to −10° C. and4-methylinorpholine was added dropwise, and stirred at −10° C. for 1hour. This solution was added to the free base solution of d,l-serinemethyl ester dropwise at −10° C. After the addition was complete, thecooling bath was removed and the resulting solution was stirred to roomtemperature for 2 hours and quenched with 1N hydrochloric acid (50 ml).The organics were separated and washed with 50 ml of saturated brinesolution, dried over magnesium sulfate, and filtered. The filtrate wasconcentrated under vacuum to a white foam which was dissolved in 40 mlether and titruated with 40 ml of hexane. The resulting white solid wasfiltered to provide 5.23 g of the desired product in 74.5% yield.

¹H NMR (CDCl₃): δ7.65 (2H, s); 7.05 (1H, d); 4.85 (1H, m); 4.05 (2H, d);3.8 (3H, s); 1.5 (18H, s); MS-FD, 351.

B.4-((RS)carbomethoxy)-2-(3,5-di-tert-butyl-4-hydroxyphenyl))-2-oxazoline

The compound of part A, above (1 g,2.85 mmole) was dissolved in 10 ml ofmethylene chloride at room temperature followed by the dropwise additionof thionyl chloride (0.23 ml, 3.13 mmole). The resulting mixture wasstirred for 2 hours at room temperature and then quenched with 10 ml ofsaturated sodium bicarbonate. The biphasic solution was then stirred for30 minutes at room temperature and the organics were separated and driedover magnesium sulfate. The drying agent was filtered and concentratedunder vacuum to give 0.75 g of a white foam in 79% yield.

¹NMR (CDCl₃): δ7.8 (2H, s); 5.6 (1H, s); 4.9 (1H, m); 4.6 (2H, m); 3.8(3H, s); 1.5 (18H, s). MS-FD, 333.

C. 4-(carbomethoxy)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazole

The compound of part B, above (5 g, 15 mmole) was dissolved in 50 ml ofdry dioxane, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.75 g, 16.5mmole) was added. The resulting solution was heated to reflux for 1.5hours, and then cooled to room temperature. The solution was filteredthrough a pad of silica gel and decolorized with activated carbon (20 g)for 16 hours. The dark solution was filtered through diatomaceous earth,and the filtrate was concentrated under vacuum to give 4.90 g of a tansolid in 98.7% yield.

¹H NMR (CDCl₃): δ8.21 (1H, s); 7.9 (2H, s); 5.6 (1H, s); 3.95 (3H, s);1.5 (18H, s). MS-FD. 331.

D. (4-(hydroxymethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl))-2-oxazole

To a slurry of lithium aluminum hydride (0.043 g, 1.1 mmol) in 10 mL drytetrahydrofuran at 0° C. was added the compound of part of C, above(0.25 g, 0.76 mmol) in one portion. The reaction was quenched after 1hour by the sequential dropwise addition of 0.25 mL water, 0.25 mL 15%NaOH and 0.75 mL water. The resulting mixture was stirred at roomtemperature for 1 hour and then filtered through celite. The pH of thefiltrate was adjusted to 7 by the addition of 1N hydrochloric acid. Themixture was extracted with ethyl acetate (2×50 mL). The organic solutionwas slurried with magnesium sulfate (0.5 g) and activated carbon (2 g)for 4 hours. The mixture was filtered through celite and concentrated byrotary evaporation to give subtitled compound (0.173 g) as an off-whitesolid.

E. Preparation of N-propyl-N-ethyl-4-hydroxyphenyl acetamide

To a solution of 4-hydroxyphenyl acetic acid (88.43 g, 653 mmol) in 700mL tetrahydrofuran at −50° C. was added a solution of 4-methylmorpholine(66.1 g, 653 mmol) in 30 mL tetrahydrofuran. iso-Butylchloroformate(89.3 g, 653 mmol) was added to the mixture and the resulting solutionwas stirred at −50° C. for 2 hours. A solution of ethylpropylamine (57g, 654 mmol) in 30 mL of tetrahydrofuran was added over 15 minutes.After 3 hours, the reaction mixture was poured into a 1:1 mixture ofethyl acetate and 1N hydrochloric acid. The ethyl acetate layer waswashed with sodium bicarbonate and brine, then dried over sodiumsulfate, filtered and concentrated to give a clear colorless oil (135g). Purification of the technical grade material was accomplished bycrystallization from ethyl acetate.

Spectral data was collected from a 1:1 mixture of amide rotamers. ¹H NMR(CDCl₃, 300 MHz) δ8.2 (br s, 1H), 7.01 (m, 2H), 6.7 (d, 2H, J=12 Hz),3.65 (s, 2H), 3.64 (s, 2H), 3.3 (m, 4H), 1.6 (m, 2H), 1.1 (m, 3H), 0.89(t, 3H, J=7 Hz).

F. Preparation of N-propyl-N-ethyl-4-hydroxyphenylethyl amine

A three neck flask fit with a condensor, addition funnel and Dean-Starktrap was charged with a solution of the compound of part E, above,(48.6, 220 mmol) in 250 mL tetrahydrofuran and heated to 50° C. Boranedimethylsulfide (10.0-10.2M, 86 mL) was added dropwise. After completeaddition, the mixture was heated to reflux for 3 hours with removal ofapproximately 60 mL of the distillate by means of the Dean Stark trap.The reaction mixture was then concentrated by distillation toapproximately 25% of the original volume. Methanol (150 mL) was slowlyadded to the mixture. The resulting mixture was heated to reflux for 30minutes and then concentrated by distillation to 50 mL total volume. Thesolution was cooled to room temperature and a 0.77M hydrochloride acidsolution in methanol (285 mL) was added. The resulting mixture wasconcentrated by rotary evaporation to a white solid. The residue wasslurried in ethyl acetate (1% methanol) and heated to reflux. Themixture was cooled and filtered to give the hydrochloric salt of desiredproduct (42 g) as a white solid.

¹H NMR (DMSO, 300 MHz) δ10.84 (br s, 1H), 9.43 (s, 1H), 7.08 (d, 2H, J=8Hz), 6.73 (d, 2H, J=8 Hz), 3.13 (m, 4H), 2.94 (m, 4H), 1.7 (m, 2H), 1.24(t, 3H, J=7 Hz), 0.9 (t, 3H, 7 Hz).

A portion of this material (26 g) was free-based by partitioning betweenethyl acetate and a sodium hydroxide solution to Ph 8. The organic phasewas dried over sodium sulfate, filtered and concentrated to yield thedesired product as a clear colorless oil (24 g).

G. 4-(bromomethyl)-2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazole

To a solution of the compound of part D, above, in −3 mL drydichloromethene at 0° C., was added phosphorus tribromide (0.089 g, 0.33mmol) dropwise. The mixture was warmed to 23° C. for 1 hour and thereaction was quenched by the dropwise addition of 3 mL pH 7 buffer whichresulted in a temperature increase to 32° C. The organic phase wasdiluted with dichloromethane, and brine was added to clarify the layers.The organic solution was collected and dried over magnesium sulfate,filtered and concentrated by rotary evaporation to give sub-titledcompound (0.084 g) as a white foam.

¹H NMR (CDCl₃, 300 MHz) δ7.85 (5,2H), 7.65 (s, 1H), 5.5 (s, 1H), 4.4 (s,2H), 1.5 (s, 9H).

H. 2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-formyl-N-ethylaminoethyl)phenoxymethyl)oxazole

To a solution of the compound of part F, above, (2.22 g, 10.2 mmol) indry tetrahydrofuran was added 60% sodium hydride in mineral oil (0.513g, 12.8 mmol). The resulting mixture was stirred overnight and thecompound of part G, above. (3.75 g, 10.3 mmol) was added. The mixturewas heated to reflux for 7 hours and then cooled to 23° C. The mixturewas diluted with ethyl acetate and washed with saturated ammoniumchloride. The organic solution was dried over magnesium sulfate,filtered and concentrated to a solid which was used in the followingstep without further purification.

I. 2-(3 5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methyl-N-ethylaminoethyl)phenoxymethyl)oxazole hydrochloride

Borane dimethylsulfide (3.2 equiv) was added dropwise to a solution ofthe unpurified amide (above) in 100 mL dry tetrahydrofuran at 23° C. Theresulting mixture was heated to reflux for 5 hours, then cooled to roomtemperature. The volatiles were removed by rotary evaporation and theresidue was dissolved in methanol and heated to reflux for 1 hour. Themixture was cooled to 23° C. and hydrochloric acid in ether (10 equiv)was added The resulting mixture was stirred overnight, then heated toreflux for 4 hours. The mixture was cooled to 23° C. and the volatileswere removed under vacuum. The residue was partitioned between ethylacetate and saturated sodium bicarbonate. The organic phase was washedwith 1N hydrochloric acid and brine. A small amount of methanol wasadded to assist layer separation. The organics were dried over magnesiumsulfate, filtered and concentrated by rotary evaporation to give a foam.The residue was purified by silica gel chromatography, initially byelution with 95% acetonitrile, 3% water and 2% ammonium hydroxide. Asecond silica gel purification followed by elution with 90% chloroformand 10% methanol with 1% ammonium hydroxide which gave a white foam.

The white foam was dissolved in methylene chloride and hydrogen chloride(g) was bubbled through the mixture for 5 minutes. The mixture wasstirred overnight and the solvent was removed by rotary evaporation togive title product (2.27 g) as a white foam.

MS-FD=492.2

EXAMPLE 59 2-(3,5-di-t-buty-4-hydroxyphenyl)-4(2-(4-methylethylaminomethylphenoxy)ethyl)oxazole

A. Preparation of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-tosyloxyether)oxazole

The compound of Example 59D (50 g, 157.5 mmole) was dissolved in 500 mlof methylene chloride at room temperature. Pyridine (51 ml, 630 mmole)and dimethylaminopropylamine (1.92 g, 15.75 mmole) were added all atonce. Next tosic anhydride (64.3 g, 196.9 mmole) was added in portions.The mixture was stirred at room temperature for 30 minutes, and quenchedwith 200 ml of 1N hydrochloric acid. The mixture was separated and theorganics were dried over magnesium sulfate. The drying agent wasfiltered and the filtrate was filtered through a plug of silica gel andwashed with 1.5 L of methylene chloride. The methylene chloride wasremoved under vacuum to give a solid which was slurried in 1 L ofpetroleum ether. The solid was filtered, collected and dried in a vacuumoven at 40° C. An off-white solid was obtained (68.93 g).

Yield=92.7%

Elemental Analysis: Calculated: C 66.22, H 7.05, N 2.97 Found: C 66.38,H 7.18, N 3.14.

B. Preparation of N-methyl-N-ethyl-4-hydroxyphenylmethylamide

To a solution of p-hydroxybenzaldehyde (20.01 g, 163.9 mmol) in 400 mLof 1,2-dichloroethane was added N-methylethylamine (11.62 g, 196.7mmol). The reaction vessel was purged with nitrogen, and sodiumtriacetoxyborohydride (48.00 g, 226.0 mmol) was added as a solid. Thereaction was quenched by addition of saturated sodium bicarbonate. Theaqueous layer was washed with ethyl acetate and then the pH was adjustedto 10. The aqueous phase was extracted with ethyl acetate. The ethylacetate was washed with 1N hydrochloric acid (pH 1) and the organicphase was discarded. The pH of the aqueous phase was adjusted to 10 andthe product was extracted with ethyl acetate. The organic solution wasdried over sodium sulfate, filtered and concentrated to a white solid.

¹H NMR (CDCl₃, 300 MHz) d 9.95 (s, 1H), 7.10 (d, 2H, J=

C. Preparation of 2-(3,5-di-t-buty-4-hydroxyphenyl)-4(2-(4-methylethylaminomethylphenoxy)ethyl)oxazole

The compound of part A, above, (4.72 g, 10 mmole), was combined with acompound of part B, above (1.73 g, 10.5 mmole), and solid sodiumhydroxide (0.6 g, 15 mmole) in 43 ml dry tetrahydrofuran at roomtemperature. The resulting mixture was heated to reflux under nitrogenfor 8 hours. The mixture was cooled to room temperature and the solventswere removed under vacuum to give a residue. The residue was partitionedbetween ethyl acetate and 1N hydrochloric acid. The organic layer wasseparated and washed twice with 1N sodium hydroxide and once with brine.The organics were dried over magnesium sulfate. The drying agent wasfiltered and the filtrate was concentrated under vacuum to give 4.59 gof an oil. The oil was dissolved in methylene chloride and filteredthrough a pad of silica gel. The silica gel was washed once withmethylene chloride and once with methanol. The methanol wash wasconcentrated under vacuum to give a residue which was partitionedbetween methylene chloride and a saturated sodium bicarbonate solution.The organic layer was separated and dried over magnesium sulfate. Thedrying agent was filtered and the filtrate was concentrated to give 3.39g of the title product as a light red oil.

MS=465.4

Elemental Analysis: Calculated: C 74.96, H 8.68, N 6.03 Found: C 74.67,H 8.44, N 5.88.

Assays

The brain is only about 2% of the total body mass, yet it consumesapproximately 20% of all the inspired oxygen. Although neurons depend onoxidative metabolism for survival, a consequence of this process is theproduction of reactive compounds such as hydrogen peroxide and oxyradicals (Cohen and Werner, 1994). In site of the high vulnerability ofthe brain to oxygen radical attack, oxygen free-radical reactions andoxidative damage are in most cases held in check by antioxidant defensemechanisms under basal conditions. Pathological conditions of thecentral nervous system exist, however, where excessive amounts of oxygenfree radicals are produced that impair defense mechanisms. Unchecked,these reactive oxygen species (ROS) can lead to DNA damage, peroxidationof membrane lipids and neuronal death.

Oxidative damage caused by free radical production and lipidperoxidation as well as by products of the arachidonic acid cascade areconsidered to be primary factors in the acute stage pathology ofischemia. Increases in the amounts of free fatty acids after ischemiaand during early reperfusion can provide the substrate for lipidperoxidation and for the formation of products of the arachidonic acidcascade (Clemens, et al., Stroke, Vol. 22, No. 8, August 1991).

Several reviews have been written on the role of oxygen radicals incerebral ischemia (Braugher and Hall, 1989; Hall and Braugher 1989;Koutos, 1989, Floyd, 1990; Nelson, et al., 1992; Panetta and Clemens,1993).

Evidence has accumulated recently suggesting that free radicals may beinvolved in the genesis of Parkinson's disease (Graham, 1984; Ogawa, etal., 1993, Ben-Shackar, et al., 1992; Carillo, et al., 1993). Reportshave also appeared suggesting free-radical involvement in thepathogenesis of Alzheimer's disease and Down's syndrome (Zelman, et al.,1989. Ceballos-Pecot, et al., 1992; Andorn, et al., 1990; Subbarao, etal., 1990, McIntosh, et al., 1991.) In addition, recent reports suggestthe involvement of free radicals in the pathogenesis of ALS (Rosen, etal., 1993; McNamara and Fridovich, 1993).

The compounds of the instant invention inhibit the formation of reactiveoxygen species in a mammal and are thereby useful for treatingconditions and diseases which are believed to be induced by increasedfree radical production such as global and cerebral ischemia,Parkinson's disease, Alzheimer's disease, Down's syndrome and ALS.

Compounds of formula I have been shown to prevent ischemia-inducedneuronal cell damage as demonstrated in the following test system.

Cerebral Ischemia Model in Rats

Cerebral ischemia was produced in rats by occluding the four arteriesthat supply blood to the brain according to the following procedure.Male Wistar rats were anesthetized with Metofane and placed into astereotaxic instrument. A longitudinal incision was made on the dorsalsurface of the neck. The neck muscles were reflected to expose thedorsal surface of the spinal column. The two vertebral arteries wereexposed where they pass through the first cervical vertebra. Botharteries were permanently occluded by the application of electrocautery.After coagulation of the vertebral arteries, the rat was removed fromthe stereotaxic instrument and the surgical wound was sutured. Twolongitudinal incisions were then made on the ventral surface of theneck. The two common carotid arteries were exposed and dissected freefrom surrounding nerves and connective tissue. An atraumatic clasp,fabricated mainly from silicone rubber tubing, was placed around eachcarotid artery in a manner such that the vessel was not traumatized oroccluded. An indwelling jugular cannula was implanted into each rat fordrug delivery. The surgical wounds were then closed. The atraumaticclasps were designed in such a manner that they could be tightened toocclude the carotid arteries by pulling on a small silastic thread thatwas allowed to protrude from the wound. Circulation to the brain throughthe carotids could be restored by relieving the tension on the silasticthreads. After the surgery, the rats were allowed to recover for 24hours.

Cerebral ischemia was induced by tightening the clasps around thecarotids. During this tame, rats in which ischemia had successfully beenproduced lost the righting reflex and became unresponsive to stimuli.The period of ischemia was 20 minutes, and immediately after the 20minutes of ischemia, at the tame of reperfusion, compounds wereadministered as an intravenous bolus infection of 10 mg/kg followed by aconstant intravenous infusion of 5.0 mg/kg per hour for 20 hours. Fivedays after the ischemia, the rats were sacrificed, and the brains wereperfused, fixed with formalin and processed for histological evaluation.

One of the areas of the brain that is most susceptible to ischemiainduced damage both in the rat and the human is the CA₁ pyramidal celllayer of the hippocampus. In animals that remain unresponsive for the 20minute period of ischemia, the CA₁ pyramidal cell layer is completelydestroyed. This layer of cells was examined microscopically inhistological sections prepared from the hippocampus, brain damage wasrated according to the following scale:

0=no damage, completely intact cell layer

1=mild damage, one-third of CA₁ layer dead

2=moderate damage, two-thirds of CA₁ layer dead

3=severe damage, greater than 90% cell death

Damage in 4 sections of the dorsal hippocampus from each brain wasassessed in order to obtain an accurate estimate of damage. An averagedamage score was calculated for each treatment group. Scores fromtreated groups were compared statistically with scores from controlgroups which received only the vehicle (phosphate buffered saline) thatwas used to suspend the compounds. The level of significance wasdetermined using the Mann Whitney-U-test.

Compounds of the instant invention were tested in the above-describedassay and were found to be useful.

The following three tests are useful in predicting the ability of acompound to inhibit free radical formation which is believed to beimplicated in disease such as ischemia, Parkinson's disease, Alzheimer'sdisease, Down's syndrome and ALS.

Lipid Peroxidation Test

Compounds of formula I were shown to inhibit the formation of lipidperoxides in mammals using the test protocol described by Aruoma, etal., (1990), Free Rad. Res. Comm., 10:143, herein incorporated byreference. Compounds of the instant invention tested in the assay citedabove were found to be active.

Superoxide O₂-Secretion Test

The compounds of formula I, in addition, were tested for their abilityto inhibit superoxide O₂-secretion using the method of Lorico, et al.,(1986), Biochem. Pharmacol., 35:2443, herein incorporated by reference.Compounds of the instant invention tested in the above mentioned assaywere found to be useful.

H₂O₂ Secretion Test

Finally, using the protocol of Root, et al., (1975), J.Clin. Invet.,55:945, herein incorporated by reference, compounds of formula I weretested and found to be effective in inhibiting H₂O₂ secretion.

Pharmaceutical Formulations

As noted above, the compounds of formula I are capable of slowing theprocess of neurodegeneration associated with Parkinson's disease,Alzheimer's disease, Down's syndrome, amyotrophic lateral sclerosis andpreventing ischemia induced cell damage thereby lending themselves tothe valuable therapeutic methods claimed herein. This method comprisesadministering to a mammal in need of treatment for Parkinson's disease,Alzheimer's disease, amyotrophic lateral sclerosis or ischemia an amountof one or more compounds of formula I effective in achieving thetherapeutic effect desired.

In general, the compounds of the invention are most desirablyadministered at a concentration that will generally afford effectiveresults without causing any harmful or deleterious side effects and canbe administered either as a single unit dose, or if desired, the dosagemay be divided into convenient subunits administered at suitable timesthroughout the day.

The compounds utilized in the method of the present invention areeffective over a wide dosage range for the treatment of Parkinson'sdisease, Alzheimer's disease, ALS and ischemia induced cell damage.Thus, as used herein, the term “therapeutically effective amount” refersto a dosage range of from about 0.5 to about 150 mg/kg of body weightper day. In the treatment of adult humans, the range of about 1.0 toabout 50 mg/kg per day, is preferred. The compound is preferablyadministered as an intravenous bolus of from about 0.1 to 100 mg/kg ofbody weight followed by a constant intravenous infusion of about 0.1 to50 mg/kg per hour for a period of about 24 hours. However, it will beunderstood that the amount of the compound actually administered will bedetermined by a physician, in the light of the relevant circumstancesincluding the choice of compound to be administered, the chosen route ofadministration, the age, weight, and response of the individual patient,and the severity of the patient's symptoms, and therefore the abovedosage ranges are not intended to limit the scope of the invention inany way.

The compositions are formulated preferably in intravenous form such thateach dosage contains from about 4.5 to about 9.5 g of the activeingredient in association with one or more suitable pharmaceuticaldiluents or excipients.

The neurodegenerative diseases, Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis and Down's syndrome are chronicconditions. The term “chronic” means a deteriorating condition of slowprocess and long continuance. As such, a chronic neurodegeneratingcondition is treated when it is diagnosed and continued throughout thecourse of the disease.

Ischemia represents a phenomenon in which tissue is deprived of eitherpartial or total blood flow in conjunction with hypoxia. It may occur asan acute event or a chronic condition. The term “acute” means anexacerbated condition of short course followed by a period of remission.Thus, the treatment of ischemia induced cell damage contemplates bothacute and chronic forms. In an acute event, compound is administered atthe onset of symptoms and discontinued when the symptoms disappear. Asdescribed above, a chronic condition is treated throughout the course ofthe disease.

The compounds can be administered by a variety of routes including theoral, rectal, transdermal, subcutaneous, intravenous, intramuscular orintranasal routes. The intravenous route of administration is preferred.No matter what route of administration is chosen, such administration isaccomplished by means of pharmaceutical compositions which are preparedby techniques well known in the pharmaceutical sciences.

In making the pharmaceutical compositions, one or more activeingredients will usually be mixed with a carrier, or diluted by acarrier, or enclosed within a carrier, or diluted by a carrier, orenclosed within a carrier which may be in the form of a capsule, sachet,paper or other container. When the carrier serves as a diluent, it maybe a solid, semi-solid or liquid material which acts as a vehicle,excipient or medium for the active ingredient. Thus, the compositionscan be in the form of tablets, pills, powders, lozenges, sachets,cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols(as a solid or in a liquid medium), ointments containing for example upto 10% by weight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions and sterile packagedpowders.

Some examples of suitable carriers, excipients, and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tregacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water,saline solution, syrup, methylcellulose, methyl- andpropylhydroxybenzoates, talc, magnesium stearate and mineral oil. Theformulations can additionally include lubricating agents, wettingagents, emulsifying and suspending agents, preserving agents, sweeteningagents or flavoring agents. The compositions may be formulated so as toprovide rapid, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures well knownin the art.

The following formulation examples may employ as active ingredients anyof the compounds of formula III. The examples are illustrative only andare not intended to limit the scope of the invention in any way.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:

Quantity (mg/capsule) 2-(3,5-di-t-butyl-4-hydroxyphenyl)- 5004-(2-(4-ethylaminomethyl-phenoxy) ethyl)thiazole Starch dried 200Magnesium  10

The above ingredients are mixed and filled into hard gelatin capsules in710 mg quantities.

Formulation 2

A tablet formula is prepared using the ingredients below:

Quantity (mg/tablet) 2-(3,5-di-t-butyl-4-hydroxyphenyl)- 1004-(2-(4-dimethylaminomethyl- phenylthio)ethyl)oxazole Cellulose,microcrystalline 400 Silicon dioxide, fumed  10 Stearic acid  5

The components are blended and compressed to form tablets each weighing515 mg.

Formulation 3

Tablets each containing 50 mg of active ingredient are made up asfollows:

Quantity (mg/tablet) 2-(3,5-di-t-butyl-4-hydroxyphenyl)-   50 mg4-(2-(4-methylethylaminomethyl- phenylthio)propyl)-5-ethyl-thiazoleStarch   50 mg Microcrystalline cellulose   40 mg Polyvinylpyrrolidone  4 mg (as 10% solution in water) Sodium carboxymethyl starch  4.5 mgMagnesium stearate  0.5 mg Talc   1 mg Total  150 mg

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate and talc, previouslypassed through a No. 60 mesh U.S. Sieve, are then added to the granuleswhich, after mixing, are compressed by a tablet machine to yield tabletseach weighing 150 mg.

Formulation 4

Capsules each containing 25 mg of medicament are made as follows:

Quantity (mg/capsule) 2-(3,5-diethyl-4-hydroxyphenyl)-  25 mg4-(2-(3-dimethylaminomethyl- phenoxy)butyl)oxazole Starch  60 mgMicrocrystalline cellulose  60 mg Magnesium stearate  5 mg Total 150 mg

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

Formulation 5

Suppositories each containing 250 mg of active ingredient are made up asfollows:

Quantity (mg/suppository) 2-(3,5-di-t-butyl-4-methoxyphenyl)-   250 mg4-(2-(4-n-propylaminomethyl- phenoxy)ethyl)oxazole Saturated fatty acid2,000 mg glycericdes to

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

Formulation 6

Suspensions each containing 100 mg of medicament per 5 ml dose are madeas follows:

Quantity (mg/5 ml) 2-(3,5-di-t-butyl-4-hydroxyphenyl)-  100 mg4-(2-(4-n-hexylamimomethyl- phenylthio)methyl)oxazole Sodiumcarboxymethylcellulose   50 mg Syrup 1.25 ml Benzoic acid solution 0.10ml Flavor q.v. Color q.v. Purified water to   5 ml

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

Formulation 7

Capsules each containing 5 mg of medicament are made up as follows:

Quantity (mg/tablet) 2-(3-isopropyl-5-t-butyl-4-hydroxyphenyl)-  5 mg4-(2-(4-diethylaminomethyl- phenoxy)ethyl)oxazole Starch 164 mgMicrocrystalline cellulose 164 mg Magnesium stearate  22 mg Total 355 mg

The active ingredient, cellulose, starch and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 355 mg quantities.

Formulation 8

An intravenous formulation may be prepared as follows:

Quantity (g) 2-(3,5-di-t-butyl-4-hydroxyphenyl)- 5 g4-(2-(4-n-butylmethylaminomethyl- phenoxy)ethyl)oxazole Isotonic Saline1 g Total 6 g

The solution of the above ingredients is administered intravenously at arate of 1 ml per minute to a subject in need of treatment.

We claim:
 1. A method for treating ischemia-induced cell damage inmammals caused by stroke, myocardial infarction, cardiac arrest orduring transplantation, by administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of formula(III)

wherein: Ar is phenyl, pyridyl, tetrahydronaphthyl, benzofuranyl orchromanyl substituted with zero to two substituents selected from thegroup consisting of —(C₁-C₆)alkyl, hydroxy and halo; and substitutedwith one or two substituents selected from the group consisting of—(CH₂)_(t)R⁶,

and —(C₁-C₆ alkyl)R⁶; provided that the phenyl or pyridyl group of Armay additionally be substituted with two substituents which when takentogether with the carbon atoms to which they are attached form a phenylring; where R⁶ is —NR⁷R⁸, morpholin-1-yl, imidazol-1-yl,4,5-dihydro-1H-imidazol-2-yl, thiomorpholin-1-yl, piperazin-1-yl orpiperazin-1-yl substituted with —(C₁-C₄)alkyl or

and R⁷ and R⁸ are each individually hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(p)OH,

—(CH₂)_(p)-piperidyl, —(CH₂)_(p)S(C₁-C₆)alkyl, —(CH₂)_(p)O(C₁-C₆)alkyl,

where R⁹ is (C₁-C₆)alkyl; ═ represents a double or single bond; X is —O—or —S—; Y is —CR⁵′R⁵—, —O— or —S—, where R⁵′ is H and R⁵ is —H or —OH orR5 and R⁵′ taken together are ═O; R is H or —(C₁-C₆)alkyl; R¹ and R² areeach individually —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy or phenyl; R³ is H or—(C₁-C₆)alkyl; R⁴ is hydrogen or —OH, or when Y is —CHR⁵, R⁴ and R⁵ areeach individually H or when taken together form a bond; m is an integerfrom 0 to 2, both inclusive; q is 0 or 1; n is an integer from 0 to 4both inclusive; p is an integer from 1 to 6 both inclusive; and t is aninteger from 1 to 4 both inclusive; or a pharmaceutically acceptablesalt, hydrate or optical isomer thereof.
 2. A method for treatingischemia-induced cell damage in mammals caused by stroke, myocardialinfarction, cardiac arrest or during transplantation, by administeringto a mammal in need of such treatment a therapeutically effective amountof a compound of formula (II)

wherein: Ar is phenyl, pyridyl, or tetrahydronaphthyl substituted withzero to two substituents selected from the group consisting of—(C₁-C₆)alkyl, hydroxy and halo; and substituted with one or twosubstituents selected from the group consisting of —O(CH₂)_(t)R⁶,

and —(C₁-C₆ alkyl)R⁶; provided that the phenyl or pyridyl group of Armay additionally be substituted with two substituents which when takentogether with the carbon atoms to which they are attached form a phenylring; where R⁶ is —NR⁷R⁸, morpholin-1-yl, imidazol-1-yl,4,5-dihydro-1H-imidazol-2-yl, thiomorpholin-1-yl, piperazin-1-yl orpiperazin-1-yl substituted with —(C₁-C₄)alkyl or

and R⁷ and R⁸ are each individually hydrogen, —(C₁-C₆)alkyl,—(CH₂)_(p)OH, —(CH₂)_(p)-piperidyl, —(CH₂)_(p)S(C₁-C₆)alkyl or

═ represents a double or single bond; X is —O— or —S—; Y is —CHR⁵—, —O—or —S—; R is H or —(C₁-C₆)alkyl; R¹ and R² are each individually—(C₁-C₆)alkyl or —(C₁-C₆)alkoxy; R³ is H or —(C₁-C₆)alkyl; R⁴ ishydrogen, or when Y is —CHR⁵, R⁴ and R⁵ are each individually H or whentaken together form a bond; m is an integer from 0 to 2, both inclusive;q is 0 or 1; n is an integer from 0 to 4 both inclusive; p is an integerfrom 1 to 6 both inclusive; and t is an integer from 1 to 4 bothinclusive; or a pharmaceutically acceptable salt, hydrate or opticalisomer thereof.
 3. A method for treating ischemia-induced cell damage inmammals caused by stroke, myocardial infarction, cardiac arrest orduring transplantation, by administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of formula(I)

wherein Ar is phenyl or pyridyl substituted with zero to twosubstituents selected from the group consisting of —(C₁-C₆) alkyl,hydroxy and halo; and substituted with one or two substituents selectedfrom the group consisting of

and —(C₁-C₆) alkyl R⁶; provided that the phenyl or pyridyl group of Armay additionally be substituted with two substituents which when takentogether with the carbon atoms to which they are attached form a phenylring; where R⁶ is —NR⁷R⁸, morpholin-1-yl, imidazol-1-yl,4,5-dihydro-1H-imidazol-2-yl, thiomorpholin-1-yl, piperazin-1-yl orpiperazin-1-yl substituted with

or —(C₁-C₆)alkyl; and R⁷ and R⁸ are each individually hydrogen, —C₁-C₆alkyl, —(CH₂)_(p)OH or —(CH₂)_(p)-piperidyl; X is —O— or —S—; Y is—CHR⁵—, —O— or —S—; R is —H or (C₁-C₆)alkyl; R¹ and R² are eachindividually —(C₁-C₆)alkyl; R³ is H or —(C₁-C₆)alkyl; R⁴ is hydrogen, orwhen Y is —CHR⁵, R⁴ and R⁵ are each individually H or when takentogether form a bond; m is 0 or 1; n is an integer from 0 to 4 bothinclusive; and p is an integer from 1 to 6 both inclusive; or apharmaceutically acceptable salt, hydrate or optical isomer thereof. 4.A method for treating ischemia-induced cell damage in mammals caused bystroke, myocardial infarction, cardiac arrest or during transplantation,by administering to a mammal in need of such treatment a therapeuticallyeffective amount of2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethylphenyloxy)ethyl)oxazole;2-(3,5-di-tert-butyl-4-hydroxyphenyl))-4-((4-N-methyl-N-ethylaminomethyl)phenoxymethyl)oxazolehydrochloride;2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-((4-N-ethyl-N-propylaminoethylphenoxy)methyl)oxazolehydrochloride or2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-ethylpropylaminoethylphenoxy)ethyl)oxazole.